Optically active amine derivative and method of synthesis

ABSTRACT

A readily available and inexpensive natural α-amino acid is converted into a compound represented by formula (1), which is then reacted with an organometallic reagent represented by formula (2) to give an optically active 5-hydroxyoxazolidine represented by formula (3), which is then treated with an acid to provide an optically active aminoketone represented by formula (4). The product is then converted into an optically active aminoalcohol represented by formula (5) or (6) by, for example reduction.  
                 
 
     The above process can provide an optically active aminoalcohol represented by formula (5) or (6) useful as a production intermediate for a medicine or pesticide from a readily available and inexpensive natural α-amino acid as a starting material stereoselectively and stably with a higher optical purity and a lower cost without racemization. This invention can also provide an optically active 5-hydroxyoxazolidine represented by formula (3) and an aminoketone represented by formula (4) as important intermediates for production of the above product as well as preparation processes therefor.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to a process for preparing an opticallyactive aminoalcohol derivative useful as a production intermediate formedicines, agricultural agents and so forth; for example, a process forpreparing erythro-(1R,2S)-p-hydroxynorephedrine. This invention alsorelates to an optically active 5-hydroxyoxazolidine derivative as animportant intermediate for production of the above optically activeaminoalcohol derivative or a number of other optically active aminederivatives as well as a preparing process therefor. For example, anoptically active 5-hydroxyoxazolidine derivative according to thisinvention is also very useful as a production intermediate for an azoleantibacterial agent. A compound defined by general formula (1), (3) or(4) which has an asymmetric carbon having R¹ and an amino substituentrepresents a R— or S-form, but not a racemic mixture of the R and Sforms. A compound defined by general formula (5) or (6) having twoadjacent asymmetric carbons which have an amino and hydroxy substituentsrepresents a R—S or S—R form, but not an R—R or S—S form.

[0003] 2. Description of the Prior Art

[0004] Recently, optically active compounds have been increasinglyneeded in many applications including medicines and agricultural agents.For industrial applications, there has been strongly needed for aconvenient and inexpensive process for preparing an optically activematerial.

[0005] The following three processes are those according to the priorart for preparing an optically active aminoalcohol derivative relatingto this invention:

[0006] [1] A method, in which, after a racemic compound of the desiredcompound is chemically synthesized, it is then optically resolved via,for example, a diastereomer salt to give the desired optically activecompound. [2] A method, in which a technique for chemical or biologicalasymmetric synthesis is employed to give an optically active compoundfrom an optically inactive material. [3] A method by a so-called “chiralpool method”, in which it starts from an optically active material andthe optical active compound is obtained under prevention ofracemization.

[0007] Regarding the process in [1] as “A method, in which, after aracemic compound of the desired compound is chemically synthesized, itis then optically resolved via, for example, a diastereomer salt to givethe desired optically active compound”, an example may be a processaccording to the prior art for preparingerythro-(1R,2S)-p-hydroxynorephedrine within a category of desiredoptically active aminoalcohol derivatives in this invention, in whichafter a racemate having the desired structure is first chemicallysynthesized, its optical resolution is carried out using an opticallyactive carboxylic acid such as D-tartaric acid (J. Med. Chem., 1977, 20,7, 978).

[0008] However, as long as using a preparation process on the basis ofoptical resolution, it is theoretically impossible to increase the yieldover 50%, unless an enantiomer is recovered and subject to a specialtreatment such as racemization. Furthermore, an optically activecarboxylic acid and the other compounds required in resolution aregenerally expensive, and it is often necessary to repeat several times aprocess such as recrystallization. In other words, the opticalresolution process requires an expensive resolving agent(s) and amultiple-stage operation, and is, therefore, industrially a high-costpreparation process.

[0009] The process in [2] as “A method, in which a technique forchemical or biological asymmetric synthesis is employed to give anoptically active compound from an optically inactive material” has beensignificantly advanced. As examples, there are mentioned an asymmetricsynthesis technique based on a chemical synthesis including the uses ofasymmetric reduction catalysts or the other agents (J. Am. Chem. Soc.,1980, 102, 7932) and an asymmetric synthesis technique based on abiotechnological synthesis using an enzyme or the other agents (JapanesePatent Laid-open No. 62-29998). Unfortunately, specificity for eachsubstrate is significantly involved in practical production and thus theprocess cannot be applied to all kinds of production. Furthermore, theprocess cannot be always inexpensive when requiring an expensiveasymmetric catalyst. In practice, for an optically active aminoalcoholderivative as a desired compound in this invention, there has beenavailable no industrially reasonable preparation processes on the basisof chemical or biotechnological technique as described above.

[0010] For the process in [3] as “A method by a so-called “chiral poolmethod”, in which it starts from an optically active material and theoptical active compound is obtained under prevention of racemization”,there have been many problems to be solved; for example, control ofracemization is difficult till now and furthermore, practical productionrequires multiple steps. Regarding the aminoalcohol derivatives as thedesired compounds in the present invention, no processes have beenreported till now, which is fully satisfactory in the industrialviewpoint.

[0011] Regarding the prior art techniques for production of theoptically active aminoalcohol derivatives, only the processes, which aredifficult in the industrial viewpoint and require considerably highcost. Therefore, a novel, inexpensive and more convenient processes forthe production are strongly desired.

[0012] Furthermore, only the following processes [4] to [6] are known inthe prior art for preparation of an optically active5-hydroxyoxazolidine derivative as an important production intermediatein the process of this invention:

[0013] [4] A method, in which(4S)-N-(ethoxycarbonyl)-4-(2-phenylethyl)-5-oxazolidinone is reactedwith 4-chloro-3-methoxyphenyl magnesium bromide (WO 95/09155). [5] Amethod, in which a 5-oxazolidinone derivative is reacted with ahalomethyl lithium (WO 00/53571). [6] A method, in which a5-oxazolidinone derivative is reacted with(trifluoromethyl)trimethylsilane (J. Org. Chem. 1998, 63 (15), 5179).

[0014] In the above [4], the compound as a starting material is aspecial synthetic, non-naturally, compound relating to amino-acids,which has a phenylethyl group in its side chain. The compound is,therefore, prepared by a multistep reaction and it is difficult toobtain the compound in general. In addition, it is not an inexpensivematerial in the viewpoint of its production cost and the processmaintains a significant problem in raw material supply. Furthermore, inthe above process [4], the process is extremely limited, as a singleproduction example, to that of the compound having a4-chloro-3-methoxyphenyl group at 5-position in the oxazolidinone ringas a principal structure, and the product is used only as a startingmaterial for a limited application to produce a medicine (Sch39166). Itcannot be said that the preparation process as an example described in[4] is a universal process, and that, regarding an optically active5-hydroxyoxazolidine derivative, which is widely useful, its preparationprocess has been fully established.

[0015] Regarding the compounds described in above [5] or [6], a specialfunctional group such as a haloalkyl group (for example, a chloromethylgroup) and a trifluoromethyl group is reacted at the 5-position of theoxazolidine as a main structure, but neither aryl nor hetero ring, whichare widely useful for an intermediate of a medicine and agriculturalagent are not included.

[0016] Although an optically active aminoalcohol derivative having anaryl group or heterocycle has been increasingly demanded in manyapplications such as in the pharmaceutical and agricultural fields, nogeneral production methods has been found in the prior art, regardingthe optically active 5-hydroxyoxazolidine derivative having an arylgroup or heterocycle at the 5-position as its important productionintermediate.

[0017] As a known prior art for preparation of an optically activeaminoketone relating to this invention, a process is known, which uses areaction where a carboxyl group in an N-protected amino acid isconverted into an acid chloride, which then undergoes Friedel-Craftsreaction (J. Am. Chem. Soc. 1981, 103, 6157). Acylation usingFriedel-Crafts reaction is, however, not considered to be a generalpreparation method for the reasons that the reaction causesracemization, that the reaction is considerably restricted by astructure to be acylated and that sometimes an aminoketone producedcannot be isolated. Thus, an industrially practical process is needed.

SUMMARY OF THE INVENTION

[0018] An objective of this invention is to provide a stereoselectivelprocess for preparing an optically active aminoalcohol derivativerepresented by the general formula (5), which is useful as a productionintermediate for a medicine or agricultural agent using a “readilyavailable and inexpensive natural α-amino acid” as a starting materialwithout racemization. Another objective is to provide technique toprepare the compound stably in a large scale with an adequate opticalpurity and a lower cost in an industrial viewpoint. Another objective isto provide a novel optically active 5-hydroxyoxazolidine derivativerepresented by general formula (3) and a novel aminoketone derivativerepresented by general formula (4) as important intermediates forproduction of the above optically active aminoalcohol derivative or manyoptically active amine derivatives other than the above compound as wellas a novel preparation process therefor.

[0019] After intensive investigation to achieve the above objects, thepresent inventors have found a process for preparing an optically activeaminoalcohol derivative represented by general formula (5), as a veryimportant production intermediate for a medicine or agricultural agent,from an inexpensive and easily available starting material.Specifically, the present inventors have newly found a process forpreparing the compound stereoselectively by a short process whilepreventing racemization, using a “natural α-L-amino acid which isindustrially available with a lower cost in a large amount” and a“natural α-D-amino acid which is industrially available with a lowercost in a large amount by racemization and optical resolution of anatural a-L-amino acid or selective assimilation (Japanese PatentLaid-open No. 63-198997) as starting materials.

[0020] In other words, the present inventors have found an industriallyvery useful novel preparation process for an optically activeaminoalcohol derivative, which is produced stably even in a large scaleproduction, as well as with a higher optical purity and at a lower cost.

[0021] Furthermore, the present inventors have found a novel opticallyactive 5-hydroxyoxazolidine derivative represented by general formula(3) having an aryl group or heterocycle at the 5-position in anoxazolidine ring, which is an important intermediate for preparing theabove optically active aminoalcohol derivative and a novel preparationprocess therefore; and a novel aminoketone derivative represented bygeneral formula (4) and a novel preparation process therefore.

[0022] Thus, the present invention has been completed.

[0023] This invention includes the following embodiments:

[0024] (I) A process for preparing an optically active aminoalcoholderivative, wherein an optically active 5-oxazolidinone derivativerepresented by a general formula (1):

[0025] wherein R¹ represents an unprotected or optionally protected sidechain in a natural α-amino acid; and R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl;

[0026] is reacted with an organometallic reagent represented by generalformula (2):

R³—M  (2)

[0027] wherein R³ represents optionally substituted aryl or optionallysubstituted heterocycle; M represents one selected from the groupconsisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen;

[0028] to form an optically active 5-hydroxyoxazolidine derivativerepresented by general formula (3):

[0029] wherein R¹, R² and R³ have the same meaning as defined above;

[0030] which is then treated under acidic conditions to give anoptically active aminoketone derivative represented by general formula(4):

[0031] wherein R¹ and R³ have the same meanings as defined above; and R⁴represents hydrogen or optionally substituted alkyloxycarbonyl,optionally substituted aryloxycarbonyl or optionally substitutedaralkyloxycarbonyl as a protective group;

[0032] which is then treated with a reducing agent or catalyticallyhydrogenated with a metal catalyst to stereoselectively provide anoptically active aminoalcohol derivative represented by general formula(5):

[0033] wherein R¹, R³ and R⁴ have the same meanings as defined above;provided that configuration of R¹ attached to the asymmetric carbon at4-position and the substituent represented by a nitrogen atom in theoptically active 5-oxazolidinone derivative represented by generalformula (1) is not changed throughout these reactions and relativeconfiguration between the amino group and the hydroxy group in theoptically active aminoalcohol derivative represented by general formula(5) is an erythro configuration.

[0034] (II) A process for preparing an aminoalcohol derivative, whereinan optically active 5-oxazolidinone derivative represented by a generalformula (1):

[0035] wherein R¹ represents an unprotected or optionally protected sidechain in a natural α-amino acid; and R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl; is reacted with an organometallic reagent represented bygeneral formula (2):

R³—M  (2)

[0036] wherein R³ represents optionally substituted aryl or optionallysubstituted heterocycle; M represents one selected from the groupconsisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen,

[0037] to form an optically active 5-hydroxyoxazolidine representedderivative by general formula (3):

[0038] wherein R¹, R² and R³ have the same meanings as defined above;

[0039] which is then treated under acidic conditions to give anoptically active aminoketone derivative represented by general formula(4):

[0040] wherein R¹ and R³ have the same meanings as defined above; and R⁴represents hydrogen or optionally substituted alkyloxycarbonyl,optionally substituted aryloxycarbonyl or optionally substitutedaralkyloxycarbonyl as a protective group;

[0041] which is then treated with a reducing agent or catalyticallyhydrogenated with a metal catalyst to provide an optically activeaminoalcohol derivative represented by general formula (5):

[0042] wherein R¹, R³ and R⁴ have the same meanings as defined above,

[0043] and then, when R⁴ is a protective group, the amino group in theproduct is deprotected to give an optically active aminoalcoholderivative represented by general formula (6):

[0044] wherein R¹ and R³ have the same meanings as defined above;

[0045] provided that configuration of R¹ attached to the asymmetriccarbon at 4-position and the substituent represented by a nitrogen atomin the optically active 5-oxazolidinone derivative represented bygeneral formula (1) is not changed throughout these reactions andrelative configuration between the amino group and the hydroxy group inthe optically active aminoalcohol derivative represented by generalformula (6) is an erythro configuration.

[0046] (III) The process for preparing an optically active aminoalcoholderivative as described in (I) or (II), wherein R¹ represents methyl,isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl,phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl oralkyloxycarbonylethyl; R² represents benzyl, tert-butyl, methyl, ethyl,isopropyl or 9-fluorenylmethyl.

[0047] (IV) The process for preparing an optically active aminoalcoholas described in (I) or (II), wherein R³ is represented by generalformula (7):

[0048] wherein Y represents halogen; or by general formula (8):

[0049] wherein R⁵ represents hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aralkyl,optionally substituted phenyl, optionally substituted heterocycle oroptionally substituted heterocyclealkyl.

[0050] (V) The process for preparing an optically active aminoalcohol asdescribed in (I) or (II) wherein R¹ represents methyl; and R³ isrepresented by general formula (8).

[0051] (VI) An optically active 5-hydroxyoxazolidine derivativerepresented by general formula (3):

[0052] wherein R¹ represents an unprotected side chain or optionallyprotected side chain in a natural α-amino acid; R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl; and R³ represents optionally substituted aryl or optionallysubstituted heterocycle.

[0053] (VII) The optically active 5-hydroxyoxazolidine derivative asdescribed in (VI), wherein R¹ represents methyl, isopropyl, isobutyl,benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl,methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl.

[0054] (VIII) The optically active 5-hydroxyoxazolidine derivative asdescribed in (VI) or (VII) wherein R² represents benzyl, tert-butyl,methyl, ethyl, isopropyl or 9-fluorenylmethyl.

[0055] (IX) The optically active 5-hydroxyoxazolidine as described in(VIII) wherein R³ is represented by general formula (7):

[0056] wherein Y represents halogen; or general formula (8):

[0057] wherein R⁵ represents hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aralkyl,optionally substituted phenyl, optionally substituted heterocycle oroptionally substituted heterocyclealkyl.

[0058] (X) The optically active 5-hydroxyoxazolidine as described in(IX) wherein R¹ is methyl.

[0059] (XI) A process for preparing an optically active5-hydroxyoxazolidine wherein an optically active 5-oxazolidinonederivative represented by general formula (1):

[0060] wherein R¹ represents an unprotected side chain or optionallyprotected side chain in a natural α-amino acid; R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl;

[0061] is reacted with an organometallic reagent represented by generalformula (2):

R³—M  (2)

[0062] wherein R³ represents optionally substituted aryl or optionallysubstituted heterocycle; M is one selected from the group consisting ofLi, MgX, ZnX, TiX₃ and CuX; and X represents halogen; to provide anoptically active 5-hydroxyoxazolidine derivative represented by generalformula (3):

[0063] wherein R¹, R² and R³ have the same meanings as defined above.

[0064] (XII) The process for preparing an optically active5-hydroxyoxazolidine derivative as described in (XI) wherein R¹represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl,benzyloxymethyl, phenylthiomethyl, methylthiomethyl,alkyloxycarbonylmethyl or alkyloxycarbonylethyl.

[0065] (XIII) The process for preparing an optically active5-hydroxyoxazolidine derivative as described in (XI) or (XII) wherein R²represents benzyl, tert-butyl, methyl, ethyl, isopropyl or9-fluorenylmethyl.

[0066] (XIV) The process for preparing an optically active5-hydroxyoxazolidine derivative as described in (XIII) wherein R³ isrepresented by general formula (7):

[0067] wherein Y represents halogen; or general formula (8):

[0068] wherein R⁵ represents hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aralkyl,optionally substituted phenyl, optionally substituted heterocycle oroptionally substituted heterocyclealkyl.

[0069] (XV) The process for preparing an optically active5-hydroxyoxazolidine derivative as described in (XIV) wherein R¹ ismethyl.

[0070] (XVI) The process for preparing an optically active5-hydroxyoxazolidine derivative as described in (XI) or (XII) wherein Min general formula (2) is MgX wherein X is as defined above.

[0071] (XVII) An aminoketone represented by general formula (4a):

[0072] wherein R^(1a) represents methyl: R^(4a) represents hydrogen,benzyloxycarbonyl, tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl;R^(3a) represents 4-benzyloxyphenyl, 4-methoxyphenyl,2,4-difluorophenyl, 2,4-dichlorophenyl or 3-indolyl.

[0073] (XVIII) A process for preparing an aminoketone derivative whereina 5-hydroxyoxazolidine derivative represented by general formula (3):

[0074] wherein R¹ represents an unprotected side chain or optionallyprotected side chain in a natural α-amino acid; R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl; and R³ represents optionally substituted aryl or optionallysubstituted heterocycle; is treated under acidic conditions to form anaminoketone derivative represented by general formula (4):

[0075] wherein R¹ and R³ are as defined above; R⁴ represents hydrogen oroptionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group.

[0076] (XIX) An optically active alcohol derivative represented bygeneral formula (5a):

[0077] wherein R^(1a) represents methyl; R^(3b) represents4-benzyloxyphenyl; R^(4b) represents benzyloxycarbonyl; andconfiguration between the amino group and the hydroxy group is erythro.

[0078] (XX) A process for preparing an optically active aminoalcoholderivative wherein an optically active aminoketone represented bygeneral formula (4b):

[0079] wherein R¹ represents an unprotected side chain or optionallyprotected side chain in a natural α-amino acid; R⁴ represents hydrogenor optionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group; R^(3c) is represented by general formula (8):

[0080] R⁵ represents hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted phenyl, optionally substituted heterocycle or optionallysubstituted heterocyclealkyl;

[0081] is treated with a reducing agent or catalytically hydrogenatedwith a metal catalyst, to stereoselectively form an optically activeaminoalcohol derivative represented by general formula (5b):

[0082] wherein R¹, R^(3c) and R⁴ are as defined above; provided thatconfiguration of R¹ attached to the asymmetric carbon at the 2-positionand the substituent represented by a nitrogen atom in the opticallyactive aminoketone derivative represented by general formula (4b) is notchanged throughout these reactions and relative configuration betweenthe amino group and the hydroxy group in the optically activeaminoalcohol derivative represented by general formula (5b) is erythro.

[0083] (XXI) A process for preparing an optically active aminoalcoholwherein an optically active aminoketone derivative represented bygeneral formula (4b):

[0084] wherein R¹ represents an unprotected side chain or optionallyprotected side chain in a natural α-amino acid; R⁴ represents hydrogenor optionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group; R^(3c) is represented by general formula (8):

[0085] R⁵ represents hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted phenyl, optionally substituted heterocycle or optionallysubstituted heterocyclealkyl;

[0086] is treated with a reducing agent or catalytically hydrogenatedwith a metal catalyst, to stereoselectively form an optically activeaminoalcohol derivative represented by general formula (5b):

[0087] wherein R¹, R^(3c) and R⁴ are as defined above, and when R⁴ is aprotective group, the amino group in the product is deprotected to givean optically active aminoalcohol derivative represented by generalformula (6a):

[0088] wherein R¹ and R^(3c) are as defined above; provided thatconfiguration of R¹ attached to the asymmetric carbon at the 2-positionand the substituent represented by a nitrogen atom in the opticallyactive aminoketone derivative represented by general formula (4b) is notchanged throughout these reactions and relative configuration betweenthe amino group and the hydroxy group in the optically activeaminoalcohol derivative represented by general formula (6a) is erythro.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0089] This invention will be detailed.

[0090] The term “unprotected side chain or optionally protected sidechain in a natural α-amino acid” as used herein refers to a side chainon an α-carbon such as alanine, valine, leucine, isoleucine, serine,threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine,hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine,tyrosine, tryptophan, histidine and ornithine for, for example, an“unprotected side chain in a natural α-amino acid”.

[0091] An “optionally protected side chain” may be a side chain on anα-carbon in any of the above natural α-amino acid in which a givenfunctional group is protected by a protective group. The protectivegroup may be any of those commonly used in a process known by thoseskilled in the art. For example, it may be a protective group for anamino, thiol, hydroxy, phenol or carboxyl group used in commonpreparation of an amino acid.

[0092] An “optionally substituted alkyl” means a substituted alkyl at anoptional position(s). Examples of the alkyl group include methyl, ethyl,isopropyl, tert-butyl, pentyl, hexyl, octyl, decyl and allyl. Examplesof the substituents used include hydroxy; alkoxys such as methoxy,benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl;alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine,chlorine, bromine and iodine.

[0093] An “optionally substituted aryl” means a substituted aryl at anoptional position(s). Examples of the aryl group include phenyl,naphthyl, anthracenyl, fluorenyl and phenanthrenyl. Examples of asubstituent(s) used include alkyls such as methyl, tert-butyl andbenzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl;phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy;phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl;and halogens such as fluorine, chlorine, bromine and iodine.

[0094] An “optionally substituted aralkyl” means a substituted aralkylat an optional position(s). Examples of the aralkyl group includebenzyl, naphthylmethyl, phenylethyl and 9-fluorenylmethyl. Examples of asubstituent(s) used include alkyls such as methyl, tert-butyl andbenzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl;phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy;phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl;and halogens such as fluorine, chlorine, bromine and iodine.

[0095] An “optionally substituted heterocycle” means an substitutedheterocycle at an optional position(s).

[0096] Examples of the heterocycle include tetrahydropyranyl,tetrahydrofuranyl, tetrahydrothienyl, piperidyl, morpholinyl,piperazinyl, pyrrolyl, furyl, thienyl, pyridyl, furfuryl, thenyl,pyridylmethyl, pyrimidyl, pyrazyl, imidazoyl, imidazoylmethyl, indolyl,indolylmethyl, isoquinolyl, quinolyl and thiazolyl. Examples of asubstituent used include alkyls such as methyl, tert-butyl and benzyl;cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl; phenyl;hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy;nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; andhalogens such as fluorine, chlorine, bromine and iodine.

[0097] A “heterocyclealkyl” in an optionally substitutedheterocyclealkyl means an alkyl substituted with one or moreheterocycles at one or more positions, and the “heterocyclealkyl” itselfis optionally substituted. Examples of the heterocycle, the alkyl andthe substituent therefor may be those described above for an “optionallysubstituted alkyl” and an “optionally substituted heterocycle”.

[0098] An “optionally substituted alkyloxycarbonyl” means an optionallysubstituted alkyloxycarbonyl at given one or more positions. Examples ofthe alkyloxycarbonyl include methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl andallyloxycarbonyl. Examples of the substituent(s) used include hydroxy;alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro;amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogenssuch as fluorine, chlorine, bromine and iodine.

[0099] An “optionally substituted aryloxycarbonyl” means an optionallysubstituted aryloxycarbonyl at given one or more positions. Examples ofthe aryloxycarbonyl include phenoxycarbonyl, naphthyloxycarbonyl,anthracenyloxycarbonyl, fluorenyloxycarbonyl andphenanthrenyloxycarbonyl. Examples of the substituent(s) used includealkyls and aralkyls such as methyl, tert-butyl and benzyl; cycloalkylsderived from cyclopropane, cyclopentane and cyclohexane (for example,cyclopropyl, cyclopentyl and cyclohexyl); phenyl; hydroxy; alkoxys suchas methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide;carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such asfluorine, chlorine, bromine and iodine.

[0100] An “optionally substituted aralkyloxycarbonyl” means anoptionally substituted aralkyloxycarbonyl at given one or morepositions. Examples of the aralkyloxycarbonyl include benzyloxycarbonyl,naphthylmethyloxycarbonyl, phenylethyloxycarbonyl and9-fluorenylmethyloxycarbonyl. Examples of the substituent(s) usedinclude alkyls and aralkyls; such as methyl, tert-butyl and benzyl;cycloalkyls derived from cyclopropane, cyclopentane and cyclohexane (forexample, cyclopropyl, cyclopentyl and cyclohexyl); phenyl; hydroxy;alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro;amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogenssuch as fluorine, chlorine, bromine and iodine.

[0101] Each of the above optionally substituted groups may have one ormore substituents. When it has a plurality of substituents, eachsubstituent may be independently selected from those described above.

[0102] A “halogen” may be fluorine, chlorine, bromine or iodine. Two“Ys” in general formula (7) may be the same or different.

[0103] A “reducing agent” means a reagent which can reduce a ketonemoiety in the aminoketone derivative represented by general formula (4)into an alcohol moiety, including borane reagents such asborane-tetrahydrofuran complex; borohydride reagents such as sodiumborohydride, zinc borohydride and sodium trimethoxy borohydride;alkylaluminum reagents such as diisopropylaluminum hydride; aluminumhydride reagents such as lithium aluminum hydride and lithiumtrialkoxyaluminum hydride; silane reagents such as trichlorosilane andtriethylsilane; sodium metal in liquid ammonia; and magnesium metal inan alcohol.

[0104] “Catalytic hydrogenation with a metal catalyst” means reductionof a ketone moiety in the aminoketone derivative represented by generalformula (4) into an alcohol moiety by catalytic hydrogenation in thepresence of a metal catalyst. Examples of the metal catalyst includenickel catalysts such as Raney nickel, platinum catalysts such asplatinum oxide, palladium catalysts such as palladium-carbon or rhodiumcatalysts such as chlorotris(triphenylphosphine)rhodium which is alsoknown as a Wilkinson catalyst.

[0105] “Erythro configuration” is a term indicating a relativeconfiguration of two adjacent asymmetric carbons. For a compoundrepresented by general formula (5) or (6), when the amino and thehydroxy groups as substituents are in the same side in a Ficherprojection formula, they have erythro configuration.

[0106] Tables 1 to 21 show representative optically active5-hydroxyoxazolidine derivatives within general formula (3); Tables 22to 27 show representative optically active aminoketone derivativeswithin general formula (4); and Tables 28 to 39 show representativeoptically active aminoalcohol derivatives within general formula (5) or(6), but this invention is not limited to these exemplified compounds.In these Tables, Ph is phenyl or phenylene; Me is methyl; Boc istert-butoxycarbonyl as a protective group. TABLE 1

Example Compound No. R2— R3— 1001 PhCH₂— p-PhCH₂OPh— 1002 CH₃—p-PhCH₂OPh— 1003 9-Fluorenylmethyl- p-PhCH₂OPh— 1004 (CH₃)₃C—o-PhCH₂OPh— 1005 CH₃— m-PhCH₂OPh— 1006 PhCH₂— p-NO₂Ph— 1007 (CH₃)₃C—p-MeOPh— 1008 PhCH₂— p-HOPh— 1009 (CH₃)₃C— Ph— 1010 PhCH₂— p-FPh 1011PhCH₂— 3-Indolyl- 1012 CH₃— 3-Indolyl- 1013 PhCH₂—

1014 PhCH₂—

1015 (CH₃)₃C— p-PhCH₂OPh— 1016 CH₃CH₂— p-PhCH₂OPh— 1017 PhCH₂—o-PhCH₂OPh— 1018 (CH₃)₃C— m-PhCH₂OPh— 1019 CH₃CH₂— o-PhCH₂OPh— 1020PhCH₂— p-MeOPh— 1021 (CH₃)₃C— m-MeOPh— 1022 PhCH₂— Ph 1023 PhCH₂—p-CH₃Ph— 1024 (CH₃)₃C— p-ClPh— 1025 (CH₃)₃C— 3-Indolyl- 10269-Fluorenylmethyl- 3-Indolyl- 1027 (CH₃)₃C—

1028 9-Fluorenylmethyl-

1029 (CH₃)₃C—

1030 PhCH₂—

1031 (CH3)₂CH—

[0107] TABLE 2

Example Compound No. R2— R3— 2001 PhCH₂— p-PhCH₂OPh— 2002 CH₃—p-PhCH₂OPh— 2003 9-Fluorenylmethyl- p-PhCH₂OPh— 2004 (CH₃)₃C—o-PhCH₂OPh— 2005 CH₃— m-PhCH₂OPh— 2006 PhCH₂— p-NO₂Ph— 2007 (CH₃)₃C—p-MeOPh— 2008 PhCH₂— p-HOPh— 2009 (CH₃)₃C— Ph— 2010 PhCH₂— p-FPh 2011PhCH₂— 3-Indolyl- 2012 CH₃— 3-Indolyl- 2013 PhCH₂—

2014 PhCH₂—

2015 (CH₃)₃C— p-PhCH₂OPh— 2016 CH₃CH₂— p-PhCH₂OPh— 2017 PhCH₂—o-PhCH₂OPh— 2018 (CH₃)₃C— m-PhCH₂OPh— 2019 CH₃CH₂— o-PhCH₂OPh— 2020PhCH₂— p-MeOPh— 2021 (CH₃)₃C— m-MeOPh— 2022 PhCH₂— Ph 2023 PhCH₂—p-CH₃Ph— 2024 (CH₃)₃C— p-ClPh— 2025 (CH₃)₃C— 3-Indolyl- 20269-Fluorenylmethyl- 3-Indolyl- 2027 (CH₃)₃C—

2028 9-Fluorenylmethyl-

2029 (CH₃)₃C—

2030 PhCH₂—

2031 (CH3)₂CH—

[0108] TABLE 3

Example Compound No. R2— R3— 3001 PhCH₂— p-PhCH₂OPh— 3002 CH₃—p-PhCH₂OPh— 3003 9-Fluorenylmethyl- p-PhCH₂OPh— 3004 (CH₃)₃C—o-PhCH₂OPh— 3005 CH₃— m-PhCH₂OPh— 3006 PhCH₂— p-NO₂Ph— 3007 (CH₃)₃C—p-MeOPh— 3008 PhCH₂— p-HOPh— 3009 (CH₃)₃C— Ph— 3010 PhCH₂— p-FPh 3011PhCH₂— 3-Indolyl- 3012 CH₃— 3-Indolyl- 3013 PhCH₂—

3014 PhCH₂—

3015 (CH₃)₃C— p-PhCH₂OPh— 3016 CH₃CH₂— p-PhCH₂OPh— 3017 PhCH₂—o-PhCH₂OPh— 3018 (CH₃)₃C— m-PhCH₂OPh— 3019 CH₃CH₂— o-PhCH₂OPh— 3020PhCH₂— p-MeOPh— 3021 (CH₃)₃C— m-MeOPh— 3022 PhCH₂— Ph 3023 PhCH₂—p-CH₃Ph— 3024 (CH₃)₃C— p-ClPh— 3025 (CH₃)₃C— 3-Indolyl- 30269-Fluorenylmethyl- 3-Indolyl- 3027 (CH₃)₃C—

3028 9-Fluorenylmethyl-

3029 (CH₃)₃C—

3030 PhCH₂—

3031 (CH3)₂CH—

[0109] TABLE 4

Example Compound No. R2— R3— 4001 PhCH₂— p-PhCH₂OPh— 4002 CH₃—p-PhCH₂OPh— 4003 9-Fluorenylmethyl- p-PhCH₂OPh— 4004 (CH₃)₃C—o-PhCH₂OPh— 4005 CH₃— m-PhCH₂OPh— 4006 PhCH₂— p-NO₂Ph— 4007 (CH₃)₃C—p-MeOPh— 4008 PhCH₂— p-HOPh— 4009 (CH₃)₃C— Ph— 4010 PhCH₂— p-FPh 4011PhCH₂— 3-Indolyl- 4012 CH₃— 3-Indolyl- 4013 PhCH₂—

4014 PhCH₂—

4015 (CH₃)₃C— p-PhCH₂OPh— 4016 CH₃CH₂— p-PhCH₂OPh— 4017 PhCH₂—o-PhCH₂OPh— 4018 (CH₃)₃C— m-PhCH₂OPh— 4019 CH₃CH₂— o-PhCH₂OPh— 4020PhCH₂— p-MeOPh— 4021 (CH₃)₃C— m-MeOPh— 4022 PhCH₂— Ph 4023 PhCH₂—p-CH₃Ph— 4024 (CH₃)₃C— p-ClPh— 4025 (CH₃)₃C— 3-Indolyl- 40269-Fluorenylmethyl- 3-Indolyl- 4027 (CH₃)₃C—

4028 9-Fluorenylmethyl-

4029 (CH₃)₃C—

4030 PhCH₂—

4031 (CH3)₂CH—

[0110] TABLE 5

Example Compound No. R2— R3— 5001 PhCH₂— p-PhCH₂OPh— 5002 CH₃—p-PhCH₂OPh— 5003 9-Fluorenylmethyl- p-PhCH₂OPh— 5004 (CH₃)₃C—o-PhCH₂OPh— 5005 CH₃— m-PhCH₂OPh— 5006 PhCH₂— p-NO₂Ph— 5007 (CH₃)₃C—p-MeOPh— 5008 PhCH₂— p-HOPh— 5009 (CH₃)₃C— Ph— 5010 PhCH₂— p-FPh 5011PhCH₂— 3-Indolyl- 5012 CH₃— 3-Indolyl- 5013 PhCH₂—

5014 PhCH₂—

5015 (CH₃)₃C— p-PhCH₂OPh— 5016 CH₃CH₂— p-PhCH₂OPh— 5017 PhCH₂—o-PhCH₂OPh— 5018 (CH₃)₃C— m-PhCH₂OPh— 5019 CH₃CH₂— o-PhCH₂OPh— 5020PhCH₂— p-MeOPh— 5021 (CH₃)₃C— m-MeOPh— 5022 PhCH₂— Ph 5023 PhCH₂—p-CH₃Ph— 5024 (CH₃)₃C— p-ClPh— 5025 (CH₃)₃C— 3-Indolyl- 50269-Fluorenylmethyl- 3-Indolyl- 5027 (CH₃)₃C—

5028 9-Fluorenylmethyl-

5029 (CH₃)₃C—

5030 PhCH₂—

5031 (CH3)₂CH—

[0111] TABLE 6

Example Compound No. R2— R3— 6001 PhCH₂— p-PhCH₂OPh— 6002 CH₃—p-PhCH₂OPh— 6003 9-Fluorenylmethyl- p-PhCH₂OPh— 6004 (CH₃)₃C—o-PhCH₂OPh— 6005 CH₃— m-PhCH₂OPh— 6006 PhCH₂— p-NO₂Ph— 6007 (CH₃)₃C—p-MeOPh— 6008 PhCH₂— p-HOPh— 6009 (CH₃)₃C— Ph— 6010 PhCH₂— p-FPh 6011PhCH₂— 3-Indolyl- 6012 CH₃— 3-Indolyl- 6013 PhCH₂—

6014 PhCH₂—

6015 (CH₃)₃C— p-PhCH₂OPh— 6016 CH₃CH₂— p-PhCH₂OPh— 6017 PhCH₂—o-PhCH₂OPh— 6018 (CH₃)₃C— m-PhCH₂OPh— 6019 CH₃CH₂— o-PhCH₂OPh— 6020PhCH₂— p-MeOPh— 6021 (CH₃)₃C— m-MeOPh— 6022 PhCH₂— Ph 6023 PhCH₂—p-CH₃Ph— 6024 (CH₃)₃C— p-ClPh— 6025 (CH₃)₃C— 3-Indolyl- 60269-Fluorenylmethyl- 3-Indolyl- 6027 (CH₃)₃C—

6028 9-Fluorenylmethyl-

6029 (CH₃)₃C—

6030 PhCH₂—

6031 (CH3)₂CH—

[0112] TABLE 7

Example Compound No. R2— R3— 7001 PhCH₂— p-PhCH₂OPh— 7002 CH₃—p-PhCH₂OPh— 7003 9-Fluorenylmethyl- p-PhCH₂OPh— 7004 (CH₃)₃C—o-PhCH₂OPh— 7005 CH₃— m-PhCH₂OPh— 7006 PhCH₂— p-NO₂Ph— 7007 (CH₃)₃C—p-MeOPh— 7008 PhCH₂— p-HOPh— 7009 (CH₃)₃C— Ph— 7010 PhCH₂— p-FPh 7011PhCH₂— 3-Indolyl- 7012 CH₃— 3-Indolyl- 7013 PhCH₂—

7014 PhCH₂—

7015 (CH₃)₃C— p-PhCH₂OPh— 7016 CH₃CH₂— p-PhCH₂OPh— 7017 PhCH₂—o-PhCH₂OPh— 7018 (CH₃)₃C— m-PhCH₂OPh— 7019 CH₃CH₂— o-PhCH₂OPh— 7020PhCH₂— p-MeOPh— 7021 (CH₃)₃C— m-MeOPh— 7022 PhCH₂— Ph 7023 PhCH₂—p-CH₃Ph— 7024 (CH₃)₃C— p-ClPh— 7025 (CH₃)₃C— 3-Indolyl- 70269-Fluorenylmethyl- 3-Indolyl- 7027 (CH₃)₃C—

7028 9-Fluorenylmethyl-

7029 (CH₃)₃C—

7030 PhCH₂—

7031 (CH3)₂CH—

[0113] TABLE 8

Example Compound No. R2— R3— 8001 PhCH₂— p-PhCH₂OPh— 8002 CH₃—p-PhCH₂OPh— 8003 9-Fluorenylmethyl- p-PhCH₂OPh— 8004 (CH₃)₃C—o-PhCH₂OPh— 8005 CH₃— m-PhCH₂OPh— 8006 PhCH₂— p-NO₂Ph— 8007 (CH₃)₃C—p-MeOPh— 8008 PhCH₂— p-HOPh— 8009 (CH₃)₃C— Ph— 8010 PhCH₂— p-FPh 8011PhCH₂— 3-Indolyl- 8012 CH₃— 3-Indolyl- 8013 PhCH₂—

8014 PhCH₂—

8015 (CH₃)₃C— p-PhCH₂OPh— 8016 CH₃CH₂— p-PhCH₂OPh— 8017 PhCH₂—o-PhCH₂OPh— 8018 (CH₃)₃C— m-PhCH₂OPh— 8019 CH₃CH₂— o-PhCH₂OPh— 8020PhCH₂— p-MeOPh— 8021 (CH₃)₃C— m-MeOPh— 8022 PhCH₂— Ph 8023 PhCH₂—p-CH₃Ph— 8024 (CH₃)₃C— p-ClPh— 8025 (CH₃)₃C— 3-Indolyl- 80269-Fluorenylmethyl- 3-Indolyl- 8027 (CH₃)₃C—

8028 9-Fluorenylmethyl-

8029 (CH₃)₃C—

8030 PhCH₂—

8031 (CH3)₂CH—

[0114] TABLE 9

Example Compound No. R2— R3— 9001 PhCH₂— p-PhCH₂OPh— 9002 CH₃—p-PhCH₂OPh— 9003 9-Fluorenylmethyl- p-PhCH₂OPh— 9004 (CH₃)₃C—o-PhCH₂OPh— 9005 CH₃— m-PhCH₂OPh— 9006 PhCH₂— p-NO₂Ph— 9007 (CH₃)₃C—p-MeOPh— 9008 PhCH₂— p-HOPh— 9009 (CH₃)₃C— Ph— 9010 PhCH₂— p-FPh 9011PhCH₂— 3-Indolyl- 9012 CH₃— 3-Indolyl- 9013 PhCH₂—

9014 PhCH₂—

9015 (CH₃)₃C— p-PhCH₂OPh— 9016 CH₃CH₂— p-PhCH₂OPh— 9017 PhCH₂—o-PhCH₂OPh— 9018 (CH₃)₃C— m-PhCH₂OPh— 9019 CH₃CH₂— o-PhCH₂OPh— 9020PhCH₂— p-MeOPh— 9021 (CH₃)₃C— m-MeOPh— 9022 PhCH₂— Ph 9023 PhCH₂—p-CH₃Ph— 9024 (CH₃)₃C— p-ClPh— 9025 (CH₃)₃C— 3-Indolyl- 90269-Fluorenylmethyl- 3-Indolyl- 9027 (CH₃)₃C—

9028 9-Fluorenylmethyl-

9029 (CH₃)₃C—

9030 PhCH₂—

9031 (CH3)₂CH—

[0115] TABLE 10

Example Compound No. R2— R3— 10001 PhCH₂— p-PhCH₂OPh— 10002 CH₃—p-PhCH₂OPh— 10003 9-Fluorenylmethyl- p-PhCH₂OPh— 10004 (CH₃)₃C—o-PhCH₂OPh— 10005 CH₃— m-PhCH₂OPh— 10006 PhCH₂— p-NO₂Ph— 10007 (CH₃)₃C—p-MeOPh— 10008 PhCH₂— p-HOPh— 10009 (CH₃)₃C— Ph— 10010 PhCH₂— p-FPh10011 PhCH₂— 3-Indolyl- 10012 CH₃— 3-Indolyl- 10013 PhCH₂—

10014 PhCH₂—

10015 (CH₃)₃C— p-PhCH₂OPh— 10016 CH₃CH₂— p-PhCH₂OPh— 10017 PhCH₂—o-PhCH₂OPh— 10018 (CH₃)₃C— m-PhCH₂OPh— 10019 CH₃CH₂— o-PhCH₂OPh— 10020PhCH₂— p-MeOPh— 10021 (CH₃)₃C— m-MeOPh— 10022 PhCH₂— Ph 10023 PhCH₂—p-CH₃Ph— 10024 (CH₃)₃C— p-ClPh— 10025 (CH₃)₃C— 3-Indolyl- 100269-Fluorenylmethyl- 3-Indolyl- 10027 (CH₃)₃C—

10028 9-Fluorenylmethyl-

10029 (CH₃)₃C—

10030 PhCH₂—

10031 (CH3)₂CH—

[0116] TABLE 1

Example Compound No. R2— R3— 11001 PhCH₂— p-PhCH₂OPh— 11002 CH₃—p-PhCH₂OPh— 11003 9-Fluorenylmethyl- p-PhCH₂OPh— 11004 (CH₃)₃C—o-PhCH₂OPh— 11005 CH₃— m-PhCH₂OPh— 11006 PhCH₂— p-NO₂Ph— 11007 (CH₃)₃C—p-MeOPh— 11008 PhCH₂— p-HOPh— 11009 (CH₃)₃C— Ph— 11010 PhCH₂— p-FPh11011 PhCH₂— 3-Indolyl- 11012 CH₃— 3-Indolyl- 11013 PhCH₂—

11014 PhCH₂—

11015 (CH₃)₃C— p-PhCH₂OPh— 11016 CH₃CH₂— p-PhCH₂OPh— 11017 PhCH₂—o-PhCH₂OPh— 11018 (CH₃)₃C— m-PhCH₂OPh— 11019 CH₃CH₂— o-PhCH₂OPh— 11020PhCH₂— p-MeOPh— 11021 (CH₃)₃C— m-MeOPh— 11022 PhCH₂— Ph 11023 PhCH₂—p-CH₃Ph— 11024 (CH₃)₃C— p-ClPh— 11025 (CH₃)₃C— 3-Indolyl- 110269-Fluorenylmethyl- 3-Indolyl- 11027 (CH₃)₃C—

11028 9-Fluorenylmethyl-

11029 (CH₃)₃C—

11030 PhCH₂—

11031 (CH3)₂CH—

[0117] TABLE 12

Example Compound No. R2— R3— 12001 PhCH₂— p-PhCH₂OPh— 12002 CH₃—p-PhCH₂OPh— 12003 9-Fluorenylmethyl- p-PhCH₂OPh— 12004 (CH₃)₃C—o-PhCH₂OPh— 12005 CH₃— m-PhCH₂OPh— 12006 PhCH₂— p-NO₂Ph— 12007 (CH₃)₃C—p-MeOPh— 12008 PhCH₂— p-HOPh— 12009 (CH₃)₃C— Ph— 12010 PhCH₂— p-FPh12011 PhCH₂— 3-Indolyl- 12012 CH₃— 3-Indolyl- 12013 PhCH₂—

12014 PhCH₂—

12015 (CH₃)₃C— p-PhCH₂OPh— 12016 CH₃CH₂— p-PhCH₂OPh— 12017 PhCH₂—o-PhCH₂OPh— 12018 (CH₃)₃C— m-PhCH₂OPh— 12019 CH₃CH₂— o-PhCH₂OPh— 12020PhCH₂— p-MeOPh— 12021 (CH₃)₃C— m-MeOPh— 12022 PhCH₂— Ph 12023 PhCH₂—p-CH₃Ph— 12024 (CH₃)₃C— p-ClPh— 12025 (CH₃)₃C— 3-Indolyl- 120269-Fluorenylmethyl- 3-Indolyl- 12027 (CH₃)₃C—

12028 9-Fluorenylmethyl-

12029 (CH₃)₃C—

12030 PhCH₂—

12031 (CH3)₂CH—

[0118] TABLE 13

Example Compound No. R2— R3— 13001 PhCH₂— p-PhCH₂OPh— 13002 CH₃—p-PhCH₂OPh— 13003 9-Fluorenylmethyl- p-PhCH₂OPh— 13004 (CH₃)₃C—o-PhCH₂OPh— 13005 CH₃— m-PhCH₂OPh— 13006 PhCH₂— p-NO₂Ph— 13007 (CH₃)₃C—p-MeOPh— 13008 PhCH₂— p-HOPh— 13009 (CH₃)₃C— Ph— 13010 PhCH₂— p-FPh13011 PhCH₂— 3-Indolyl- 13012 CH₃— 3-Indolyl- 13013 PhCH₂—

13014 PhCH₂—

13015 (CH₃)₃C— p-PhCH₂OPh— 13016 CH₃CH₂— p-PhCH₂OPh— 13017 PhCH₂—o-PhCH₂OPh— 13018 (CH₃)₃C— m-PhCH₂OPh— 13019 CH₃CH₂— o-PhCH₂OPh— 13020PhCH₂— p-MeOPh— 13021 (CH₃)₃C— m-MeOPh— 13022 PhCH₂— Ph 13023 PhCH₂—p-CH₃Ph— 13024 (CH₃)₃C— p-ClPh— 13025 (CH₃)₃C— 3-Indolyl- 130269-Fluorenylmethyl- 3-Indolyl- 13027 (CH₃)₃C—

13028 9-Fluorenylmethyl-

13029 (CH₃)₃C—

13030 PhCH₂—

13031 (CH3)₂CH—

[0119] TABLE 14

Example Compound No. R2— R3— 14001 PhCH₂— p-PhCH₂OPh— 14002 CH₃—p-PhCH₂OPh— 14003 9-Fluorenylmethyl- p-PhCH₂OPh— 14004 (CH₃)₃C—o-PhCH₂OPh— 14005 CH₃— m-PhCH₂OPh— 14006 PhCH₂— p-NO₂Ph— 14007 (CH₃)₃C—p-MeOPh— 14008 PhCH₂— p-HOPh— 14009 (CH₃)₃C— Ph— 14010 PhCH₂— p-FPh14011 PhCH₂— 3-Indolyl- 14012 CH₃— 3-Indolyl- 14013 PhCH₂—

14014 PhCH₂—

14015 (CH₃)₃C— p-PhCH₂OPh— 14016 CH₃CH₂— p-PhCH₂OPh— 14017 PhCH₂—o-PhCH₂OPh— 14018 (CH₃)₃C— m-PhCH₂OPh— 14019 CH₃CH₂— o-PhCH₂OPh— 14020PhCH₂— p-MeOPh— 14021 (CH₃)₃C— m-MeOPh— 14022 PhCH₂— Ph 14023 PhCH₂—p-CH₃Ph— 14024 (CH₃)₃C— p-ClPh— 14025 (CH₃)₃C— 3-Indolyl- 140269-Fluorenylmethyl- 3-Indolyl- 14027 (CH₃)₃C—

14028 9-Fluorenylmethyl-

14029 (CH₃)₃C—

14030 PhCH₂—

14031 (CH3)₂CH—

[0120] TABLE 15

Example Compound No. R2— R3— 15001 PhCH₂— p-PhCH₂OPh— 15002 CH₃—p-PhCH₂OPh— 15003 9-Fluorenylmethyl- p-PhCH₂OPh— 15004 (CH₃)₃C—o-PhCH₂OPh— 15005 CH₃— m-PhCH₂OPh— 15006 PhCH₂— p-NO₂Ph— 15007 (CH₃)₃C—p-MeOPh— 15008 PhCH₂— p-HOPh— 15009 (CH₃)₃C— Ph— 15010 PhCH₂— p-FPh15011 PhCH₂— 3-Indolyl- 15012 CH₃— 3-Indolyl- 15013 PhCH₂—

15014 PhCH₂—

15015 (CH₃)₃C— p-PhCH₂OPh— 15016 CH₃CH₂— p-PhCH₂OPh— 15017 PhCH₂—o-PhCH₂OPh— 15018 (CH₃)₃C— m-PhCH₂OPh— 15019 CH₃CH₂— o-PhCH₂OPh— 15020PhCH₂— p-MeOPh— 15021 (CH₃)₃C— m-MeOPh— 15022 PhCH₂— Ph 15023 PhCH₂—p-CH₃Ph— 15024 (CH₃)₃C— p-ClPh— 15025 (CH₃)₃C— 3-Indolyl- 150269-Fluorenylmethyl- 3-Indolyl- 15027 (CH₃)₃C—

15028 9-Fluorenylmethyl-

15029 (CH₃)₃C—

15030 PhCH₂—

15031 (CH3)₂CH—

[0121] TABLE 16

Example Compound No. R2— R3— 16001 PhCH₂— p-PhCH₂OPh— 16002 CH₃—p-PhCH₂OPh— 16003 9-Fluorenylmethyl- p-PhCH₂OPh— 16004 (CH₃)₃C—o-PhCH₂OPh— 16005 CH₃— m-PhCH₂OPh— 16006 PhCH₂— p-NO₂Ph— 16007 (CH₃)₃C—p-MeOPh— 16008 PhCH₂— p-HOPh— 16009 (CH₃)₃C— Ph— 16010 PhCH₂— p-FPh16011 PhCH₂— 3-Indolyl- 16012 CH₃— 3-Indolyl- 16013 PhCH₂—

16014 PhCH₂—

16015 (CH₃)₃C— p-PhCH₂OPh— 16016 CH₃CH₂— p-PhCH₂OPh— 16017 PhCH₂—o-PhCH₂OPh— 16018 (CH₃)₃C— m-PhCH₂OPh— 16019 CH₃CH₂— o-PhCH₂OPh— 16020PhCH₂— p-MeOPh— 16021 (CH₃)₃C— m-MeOPh— 16022 PhCH₂— Ph 16023 PhCH₂—p-CH₃Ph— 16024 (CH₃)₃C— p-ClPh— 16025 (CH₃)₃C— 3-Indolyl- 160269-Fluorenylmethyl- 3-Indolyl- 16027 (CH₃)₃C—

16028 9-Fluorenylmethyl-

16029 (CH₃)₃C—

16030 PhCH₂—

16031 (CH3)₂CH—

[0122] TABLE 17

Example Compound No. R2— R3— 17001 PhCH₂— p-PhCH₂OPh— 17002 CH₃—p-PhCH₂OPh— 17003 9-Fluorenylmethyl- p-PhCH₂OPh— 17004 (CH₃)₃C—o-PhCH₂OPh— 17005 CH₃— m-PhCH₂OPh— 17006 PhCH₂— p-NO₂Ph— 17007 (CH₃)₃C—p-MeOPh— 17008 PhCH₂— p-HOPh— 17009 (CH₃)₃C— Ph— 17010 PhCH₂— p-FPh17011 PhCH₂— 3-Indolyl- 17012 CH₃— 3-Indolyl- 17013 PhCH₂—

17014 PhCH₂—

17015 (CH₃)₃C— p-PhCH₂OPh— 17016 CH₃CH₂— p-PhCH₂OPh— 17017 PhCH₂—o-PhCH₂OPh— 17018 (CH₃)₃C— m-PhCH₂OPh— 17019 CH₃CH₂— o-PhCH₂OPh— 17020PhCH₂— p-MeOPh— 17021 (CH₃)₃C— m-MeOPh— 17022 PhCH₂— Ph 17023 PhCH₂—p-CH₃Ph— 17024 (CH₃)₃C— p-ClPh— 17025 (CH₃)₃C— 3-Indolyl- 170269-Fluorenylmethyl- 3-Indolyl- 17027 (CH₃)₃C—

17028 9-Fluorenylmethyl-

17029 (CH₃)₃C—

17030 PhCH₂—

17031 (CH3)₂CH—

[0123] TABLE 13

Example Compound No. R2— R3— 18001 PhCH₂— p-PhCH₂OPh— 18002 CH₃—p-PhCH₂OPh— 18003 9-Fluorenylmethyl- p-PhCH₂OPh— 18004 (CH₃)₃C—o-PhCH₂OPh— 18005 CH₃— m-PhCH₂OPh— 18006 PhCH₂— p-NO₂Ph— 18007 (CH₃)₃C—p-MeOPh— 18008 PhCH₂— p-HOPh— 18009 (CH₃)₃C— Ph— 18010 PhCH₂— p-FPh18011 PhCH₂— 3-Indolyl- 18012 CH₃— 3-Indolyl- 18013 PhCH₂—

18014 PhCH₂—

18015 (CH₃)₃C— p-PhCH₂OPh— 18016 CH₃CH₂— p-PhCH₂OPh— 18017 PhCH₂—o-PhCH₂OPh— 18018 (CH₃)₃C— m-PhCH₂OPh— 18019 CH₃CH₂— o-PhCH₂OPh— 18020PhCH₂— p-MeOPh— 18021 (CH₃)₃C— m-MeOPh— 18022 PhCH₂— Ph 18023 PhCH₂—p-CH₃Ph— 18024 (CH₃)₃C— p-ClPh— 18025 (CH₃)₃C— 3-Indolyl- 180269-Fluorenylmethyl- 3-Indolyl- 18027 (CH₃)₃C—

18028 9-Fluorenylmethyl-

18029 (CH₃)₃C—

18030 PhCH₂—

18031 (CH3)₂CH—

[0124] TABLE 19

Example Compound No. R2— R3— 19001 PhCH₂— p-PhCH₂OPh— 19002 CH₃—p-PhCH₂OPh— 19003 9-Fluorenylmethyl- p-PhCH₂OPh— 19004 (CH₃)₃C—o-PhCH₂OPh— 19005 CH₃— m-PhCH₂OPh— 19006 PhCH₂— p-NO₂Ph— 19007 (CH₃)₃C—p-MeOPh— 19008 PhCH₂— p-HOPh— 19009 (CH₃)₃C— Ph— 19010 PhCH₂— p-FPh19011 PhCH₂— 3-Indolyl- 19012 CH₃— 3-Indolyl- 19013 PhCH₂—

19014 PhCH₂—

19015 (CH₃)₃C— p-PhCH₂OPh— 19016 CH₃CH₂— p-PhCH₂OPh— 19017 PhCH₂—o-PhCH₂OPh— 19018 (CH₃)₃C— m-PhCH₂OPh— 19019 CH₃CH₂— o-PhCH₂OPh— 19020PhCH₂— p-MeOPh— 19021 (CH₃)₃C— m-MeOPh— 19022 PhCH₂— Ph 19023 PhCH₂—p-CH₃Ph— 19024 (CH₃)₃C— p-ClPh— 19025 (CH₃)₃C— 3-Indolyl- 190269-Fluorenylmethyl- 3-Indolyl- 19027 (CH₃)₃C—

19028 9-Fluorenylmethyl-

19029 (CH₃)₃C—

19030 PhCH₂—

19031 (CH3)₂CH—

[0125] TABLE 20

Example Compound No. R2— R3— 20001 PhCH₂— p-PhCH₂OPh— 20002 CH₃—p-PhCH₂OPh— 20003 9-Fluorenylmethyl- p-PhCH₂OPh— 20004 (CH₃)₃C—o-PhCH₂OPh— 20005 CH₃— m-PhCH₂OPh— 20006 PhCH₂— p-NO₂Ph— 20007 (CH₃)₃C—p-MeOPh— 20008 PhCH₂— p-HOPh— 20009 (CH₃)₃C— Ph— 20010 PhCH₂— p-FPh20011 PhCH₂— 3-Indolyl- 20012 CH₃— 3-Indolyl- 20013 PhCH₂—

20014 PhCH₂—

20015 (CH₃)₃C— p-PhCH₂OPh— 20016 CH₃CH₂— p-PhCH₂OPh— 20017 PhCH₂—o-PhCH₂OPh— 20018 (CH₃)₃C— m-PhCH₂OPh— 20019 CH₃CH₂— o-PhCH₂OPh— 20020PhCH₂— p-MeOPh— 20021 (CH₃)₃C— m-MeOPh— 20022 PhCH₂— Ph 20023 PhCH₂—p-CH₃Ph— 20024 (CH₃)₃C— p-ClPh— 20025 (CH₃)₃C— 3-Indolyl- 200269-Fluorenylmethyl- 3-Indolyl- 20027 (CH₃)₃C—

20028 9-Fluorenylmethyl-

20029 (CH₃)₃C—

20030 PhCH₂—

20031 (CH3)₂CH—

[0126] TABLE 21

Example Compound No. R2— R3— 21001 PhCH₂— p-PhCH₂OPh— 21002 CH₃—p-PhCH₂OPh— 21003 9-Fluorenylmethyl- p-PhCH₂OPh— 21004 (CH₃)₃C—o-PhCH₂OPh— 21005 CH₃— m-PhCH₂OPh— 21006 PhCH₂— p-NO₂Ph— 21007 (CH₃)₃C—p-MeOPh— 21008 PhCH₂— p-HOPh— 21009 (CH₃)₃C— Ph— 21010 PhCH₂— p-FPh21011 PhCH₂— 3-Indolyl- 21012 CH₃— 3-Indolyl- 21013 PhCH₂—

21014 PhCH₂—

21015 (CH₃)₃C— p-PhCH₂OPh— 21016 CH₃CH₂— p-PhCH₂OPh— 21017 PhCH₂—o-PhCH₂OPh— 21018 (CH₃)₃C— m-PhCH₂OPh— 21019 CH₃CH₂— o-PhCH₂OPh— 21020PhCH₂— p-MeOPh— 21021 (CH₃)₃C— m-MeOPh— 21022 PhCH₂— Ph 21023 PhCH₂—p-CH₃Ph— 21024 (CH₃)₃C— p-ClPh— 21025 (CH₃)₃C— 3-Indolyl- 210269-Fluorenylmethyl- 3-Indolyl- 21027 (CH₃)₃C—

21028 9-Fluorenylmethyl-

21029 (CH₃)₃C—

21030 PhCH₂—

21031 (CH3)₂CH—

[0127] TABLE 22

Example Compound No. R2— R3— 22001 PhCH₂— p-PhCH₂OPh— 22002 CH₃—p-PhCH₂OPh— 22003 9-Fluorenylmethyl- p-PhCH₂OPh— 22004 (CH₃)₃C—o-PhCH₂OPh— 22005 CH₃— m-PhCH₂OPh— 22006 PhCH₂— p-NO₂Ph— 22007 (CH₃)₃C—p-MeOPh— 22008 PhCH₂— p-HOPh— 22009 (CH₃)₃C— Ph— 22010 PhCH₂— p-FPh22011 PhCH₂— 3-Indolyl- 22012 CH₃— 3-Indolyl- 22013 PhCH₂—

22014 PhCH₂—

22015 (CH₃)₃C— p-PhCH₂OPh— 22016 CH₃CH₂— p-PhCH₂OPh— 22017 PhCH₂—o-PhCH₂OPh— 22018 (CH₃)₃C— m-PhCH₂OPh— 22019 CH₃CH₂— o-PhCH₂OPh— 22020PhCH₂— p-MeOPh— 22021 (CH₃)₃C— m-MeOPh— 22022 PhCH₂— Ph 22023 PhCH₂—p-CH₃Ph— 22024 (CH₃)₃C— p-ClPh— 22025 (CH₃)₃C— 3-Indolyl- 220269-Fluorenylmethyl- 3-Indolyl- 22027 (CH₃)₃C—

22028 9-Fluorenylmethyl-

22029 (CH₃)₃C—

22030 PhCH₂—

22031 (CH3)₂CH—

[0128] TABLE 23

Example Compound No. R2— R3— 23001 PhCH₂— p-PhCH₂OPh— 23002 CH₃—p-PhCH₂OPh— 23003 9-Fluorenylmethyl- p-PhCH₂OPh— 23004 (CH₃)₃C—o-PhCH₂OPh— 23005 CH₃— m-PhCH₂OPh— 23006 PhCH₂— p-NO₂Ph— 23007 (CH₃)₃C—p-MeOPh— 23008 PhCH₂— p-HOPh— 23009 (CH₃)₃C— Ph— 23010 PhCH₂— p-FPh23011 PhCH₂— 3-Indolyl- 23012 CH₃— 3-Indolyl- 23013 PhCH₂—

23014 PhCH₂—

23015 (CH₃)₃C— p-PhCH₂OPh— 23016 CH₃CH₂— p-PhCH₂OPh— 23017 PhCH₂—o-PhCH₂OPh— 23018 (CH₃)₃C— m-PhCH₂OPh— 23019 CH₃CH₂— o-PhCH₂OPh— 23020PhCH₂— p-MeOPh— 23021 (CH₃)₃C— m-MeOPh— 23022 PhCH₂— Ph 23023 PhCH₂—p-CH₃Ph— 23024 (CH₃)₃C— p-ClPh— 23025 (CH₃)₃C— 3-Indolyl- 230269-Fluorenylmethyl- 3-Indolyl- 23027 (CH₃)₃C—

23028 9-Fluorenylmethyl-

23029 (CH₃)₃C—

23030 PhCH₂—

23031 (CH3)₂CH—

[0129] TABLE 24

Example Compound No. R2— R3— 24001 PhCH₂— p-PhCH₂OPh— 24002 CH₃—p-PhCH₂OPh— 24003 9-Fluorenylmethyl- p-PhCH₂OPh— 24004 (CH₃)₃C—o-PhCH₂OPh— 24005 CH₃— m-PhCH₂OPh— 24006 PhCH₂— p-NO₂Ph— 24007 (CH₃)₃C—p-MeOPh— 24008 PhCH₂— p-HOPh— 24009 (CH₃)₃C— Ph— 24010 PhCH₂— p-FPh24011 PhCH₂— 3-Indolyl- 24012 CH₃— 3-Indolyl- 24013 PhCH₂—

24014 PhCH₂—

24015 (CH₃)₃C— p-PhCH₂OPh— 24016 CH₃CH₂— p-PhCH₂OPh— 24017 PhCH₂—o-PhCH₂OPh— 24018 (CH₃)₃C— m-PhCH₂OPh— 24019 CH₃CH₂— o-PhCH₂OPh— 24020PhCH₂— p-MeOPh— 24021 (CH₃)₃C— m-MeOPh— 24022 PhCH₂— Ph 24023 PhCH₂—p-CH₃Ph— 24024 (CH₃)₃C— p-ClPh— 24025 (CH₃)₃C— 3-Indolyl- 240269-Fluorenylmethyl- 3-Indolyl- 24027 (CH₃)₃C—

24028 9-Fluorenylmethyl-

24029 (CH₃)₃C—

24030 PhCH₂—

24031 (CH3)₂CH—

[0130] TABLE 25

Example Compound No. R2— R3— 25001 PhCH₂— p-PhCH₂OPh— 25002 CH₃—p-PhCH₂OPh— 25003 9-Fluorenylmethyl- p-PhCH₂OPh— 25004 (CH₃)₃C—o-PhCH₂OPh— 25005 CH₃— m-PhCH₂OPh— 25006 PhCH₂— p-NO₂Ph— 25007 (CH₃)₃C—p-MeOPh— 25008 PhCH₂— p-HOPh— 25009 (CH₃)₃C— Ph— 25010 PhCH₂— p-FPh25011 PhCH₂— 3-Indolyl- 25012 CH₃— 3-Indolyl- 25013 PhCH₂—

25014 PhCH₂—

25015 (CH₃)₃C— p-PhCH₂OPh— 25016 CH₃CH₂— p-PhCH₂OPh— 25017 PhCH₂—o-PhCH₂OPh— 25018 (CH₃)₃C— m-PhCH₂OPh— 25019 CH₃CH₂— o-PhCH₂OPh— 25020PhCH₂— p-MeOPh— 25021 (CH₃)₃C— m-MeOPh— 25022 PhCH₂— Ph 25023 PhCH₂—p-CH₃Ph— 25024 (CH₃)₃C— p-ClPh— 25025 (CH₃)₃C— 3-Indolyl- 250269-Fluorenylmethyl- 3-Indolyl- 25027 (CH₃)₃C—

25028 9-Fluorenylmethyl-

25029 (CH₃)₃C—

25030 PhCH₂—

25031 (CH3)₂CH—

[0131] TABLE 26

Example Compound No. R2— R3— 26001 PhCH₂— p-PhCH₂OPh— 26002 CH₃—p-PhCH₂OPh— 26003 9-Fluorenylmethyl- p-PhCH₂OPh— 26004 (CH₃)₃C—o-PhCH₂OPh— 26005 CH₃— m-PhCH₂OPh— 26006 PhCH₂— p-NO₂Ph— 26007 (CH₃)₃C—p-MeOPh— 26008 PhCH₂— p-HOPh— 26009 (CH₃)₃C— Ph— 26010 PhCH₂— p-FPh26011 PhCH₂— 3-Indolyl- 26012 CH₃— 3-Indolyl- 26013 PhCH₂—

26014 PhCH₂—

26015 (CH₃)₃C— p-PhCH₂OPh— 26016 CH₃CH₂— p-PhCH₂OPh— 26017 PhCH₂—o-PhCH₂OPh— 26018 (CH₃)₃C— m-PhCH₂OPh— 26019 CH₃CH₂— o-PhCH₂OPh— 26020PhCH₂— p-MeOPh— 26021 (CH₃)₃C— m-MeOPh— 26022 PhCH₂— Ph 26023 PhCH₂—p-CH₃Ph— 26024 (CH₃)₃C— p-ClPh— 26025 (CH₃)₃C— 3-Indolyl- 260269-Fluorenylmethyl- 3-Indolyl- 26027 (CH₃)₃C—

26028 9-Fluorenylmethyl-

26029 (CH₃)₃C—

26030 PhCH₂—

26031 (CH3)₂CH—

[0132] TABLE 24

Example Compound No. R2— R3— 27001 PhCH₂— p-PhCH₂OPh— 27002 CH₃—p-PhCH₂OPh— 27003 9-Fluorenylmethyl- p-PhCH₂OPh— 27004 (CH₃)₃C—o-PhCH₂OPh— 27005 CH₃— m-PhCH₂OPh— 27006 PhCH₂— p-NO₂Ph— 27007 (CH₃)₃C—p-MeOPh— 27008 PhCH₂— p-HOPh— 27009 (CH₃)₃C— Ph— 27010 PhCH₂— p-FPh27011 PhCH₂— 3-Indolyl- 27012 CH₃— 3-Indolyl- 27013 PhCH₂—

27014 PhCH₂—

27015 (CH₃)₃C— p-PhCH₂OPh— 27016 CH₃CH₂— p-PhCH₂OPh— 27017 PhCH₂—o-PhCH₂OPh— 27018 (CH₃)₃C— m-PhCH₂OPh— 27019 CH₃CH₂— o-PhCH₂OPh— 27020PhCH₂— p-MeOPh— 27021 (CH₃)₃C— m-MeOPh— 27022 PhCH₂— Ph 27023 PhCH₂—p-CH₃Ph— 27024 (CH₃)₃C— p-ClPh— 27025 (CH₃)₃C— 3-Indolyl- 270269-Fluorenylmethyl- 3-Indolyl- 27027 (CH₃)₃C—

27028 9-Fluorenylmethyl-

27029 (CH₃)₃C—

27030 PhCH₂—

27031 (CH3)₂CH—

[0133] TABLE 28

Example Compound No. R1— R3— 28001 CH₃— p-HOPh— 28002 CH₃— o-HOPh— 28003CH₃— m-HOPh— 28004 CH₃— p-MeOPh— 28005 CH₃— o-MeOPh— 28006 CH₃— m-MeOPh—28007 CH₃— p-MePh— 28008 CH₃— p-(CH₃)₂NPh— 28009 CH₃— Ph— 28010 CH₃—p-FPh 28011 CH₃— 3-Indolyl- 28012 CH₃— p-AcNHPh 28013 CH₃—

28014 CH₃—

28015 CH₃—

28016 (CH₃)₂CH— p-HOPh— 28017 (CH₃)₂CH— o-HOPh— 28018 (CH₃)₂CH— m-HOPh—28019 (CH₃)₂CH— p-MeOPh— 28020 (CH₃)₂CH— o-MeOPh— 28021 (CH₃)₂CH—m-MeOPh— 28022 (CH₃)₂CH— p-MePh— 28023 (CH₃)₂CH— p-(CH₃—)₂NPh— 28024(CH₃)₂CH— Ph— 28025 (CH₃)₂CH— p-FPh 28026 (CH₃)₂CH— 3-Indolyl- 28027(CH₃)₂CH— p-AcNHPh 28028 (CH₃)₂CH—

28029 (CH₃)₂CH—

28030 (CH₃)₂CH—

[0134] TABLE 29

Example Compound No. R1— R3— 29001 PhCH₂— p-HOPh— 29002 PhCH₂— o-HOPh—29003 PhCH₂— m-HOPh— 29004 PhCH₂— p-MeOPh— 29005 PhCH₂— o-MeOPh— 29006PhCH₂— m-MeOPh— 29007 PhCH₂— p-MePh— 29008 PhCH₂— p-(CH₃)₂NPh— 29009PhCH₂— Ph— 29010 PhCH₂— p-FPh 29011 PhCH₂— 3-Indolyl- 29012 PhCH₂—p-AcNHPh 29013 PhCH₂—

29014 PhCH₂—

29015 PhCH₂—

29016 HOCH₂— p-HOPh— 29017 HOCH₂— o-HOPh— 29018 HOCH₂— m-HOPh— 29019HOCH₂— p-MeOPh— 29020 HOCH₂— o-MeOPh— 29021 HOCH₂— m-MeOPh— 29022 HOCH₂—p-MePh— 29023 HOCH₂— p-(CH₃—)₂NPh— 29024 HOCH₂— Ph— 29025 HOCH₂— p-FPh29026 HOCH₂— 3-Indolyl- 29027 HOCH₂— p-AcNHPh 29028 HOCH₂—

29029 HOCH₂—

29030 HOCH₂—

[0135] TABLE 30

Example Compound No. R1— R3— 30001 CH₃— p-HOPh— 30002 CH₃— o-HOPh— 30003CH₃— m-HOPh— 30004 CH₃— p-MeOPh— 30005 CH₃— o-MeOPh— 30006 CH₃— m-MeOPh—30007 CH₃— p-MePh— 30008 CH₃— p-(CH₃)₂NPh— 30009 CH₃— Ph— 30010 CH₃—p-FPh 30011 CH₃— 3-Indolyl- 30012 CH₃— p-AcNHPh 30013 CH₃—

30014 CH₃—

30015 CH₃—

30016 (CH₃)₂CH— p-HOPh— 30017 (CH₃)₂CH— o-HOPh— 30018 (CH₃)₂CH— m-HOPh—30019 (CH₃)₂CH— p-MeOPh— 30020 (CH₃)₂CH— o-MeOPh— 30021 (CH₃)₂CH—m-MeOPh— 30022 (CH₃)₂CH— p-MePh— 30023 (CH₃)₂CH— p-(CH₃—)₂NPh— 30024(CH₃)₂CH— Ph— 30025 (CH₃)₂CH— p-FPh 30026 (CH₃)₂CH— 3-Indolyl- 30027(CH₃)₂CH— p-AcNHPh 30028 (CH₃)₂CH—

30029 (CH₃)₂CH—

30030 (CH₃)₂CH—

[0136] TABLE 31

Example Compound No. R1— R3— 31001 PhCH2— p-HOPh— 31002 PhCH2— o-HOPh—31003 PhCH2— m-HOPh— 31004 PhCH2— p-MeOPh— 31005 PhCH2— o-MeOPh— 31006PhCH2— m-MeOPh— 31007 PhCH2— p-MePh— 31008 PhCH2— p-(CH3)2NPh— 31009PhCH2— Ph— 31010 PhCH2— p-FPh 31011 PhCH2— 3-Indolyl- 31012 PhCH2—p-AcNHPh 31013 PhCH2—

31014 PhCH2—

31015 PhCH2—

31016 HOCH2— p-HOPh— 31017 HOCH2— o-HOPh— 31018 HOCH2— m-HOPh— 31019HOCH2— p-MeOPh— 31020 HOCH2— o-MeOPh— 31021 HOCH2— m-MeOPh— 31022 HOCH2—p-MePh— 31023 HOCH2— p-(CH3)2NPh— 31024 HOCH2— Ph— 31025 HOCH2— p-FPh31026 HOCH2— 3-Indolyl- 31027 HOCH2— p-AcNHPh 31028 HOCH2—

31029 HOCH2—

31030 HOCH2—

[0137] TABLE 32

Example Compound No. R1— R3— 32001 CH3— p-HOPh— 32002 CH3— p-PhCH2OPh—32003 CH3— p-MeOCH2CH2OPh— 32004 CH3— p-MeOPh— 32005 CH3— o-MeOPh— 32006CH3— m-MeOPh— 32007 CH3— p-MePh— 32008 CH3— p-(CH3)2NPh— 32009 CH3— Ph—32010 CH3— p-FPh 32011 CH3— 3-Indolyl- 32012 CH3— p-AcNHPh 32013 CH3—

32014 CH3—

32015 CH3—

32016 (CH3)2CH— p-HOPh— 32017 (CH3)2CH— p-PhCH2OPh— 32018 (CH3)2CH—p-MeOCH2CH2OPh— 32019 (CH3)2CH— p-MeOPh— 32020 (CH3)2CH— o-MeOPh— 32021(CH3)2CH— m-MeOPh— 32022 (CH3)2CH— p-MePh— 32023 (CH3)2CH— p-(CH3)2NPh—32024 (CH3)2CH— Ph— 32025 (CH3)2CH— p-FPh 32026 (CH3)2CH— 3-Indolyl-32027 (CH3)2CH— p-AcNHPh 32028 (CH3)2CH—

32029 (CH3)2CH—

32030 (CH3)2CH—

[0138] TABLE 33

Example Compound No. R1— R3— 33001 PhCH2— p-HOPh— 33002 PhCH2—p-PhCH2OPh— 33003 PhCH2— p-MeOCH2CH2OPh— 33004 PhCH2— p-MeOPh— 33005PhCH2— o-MeOPh— 33006 PhCH2— m-MeOPh— 33007 PhCH2— p-MePh— 33008 PhCH2—p-(CH3)2NPh— 33009 PhCH2— Ph— 33010 PhCH2— p-FPh 33011 PhCH2— 3-Indolyl-33012 PhCH2— p-AcNHPh 33013 PhCH2—

33014 PhCH2—

33015 PhCH2—

33016 HOCH2— p-HOPh— 33017 HOCH2— p-PhCH2OPh— 33018 HOCH2—p-MeOCH2CH2OPh— 33019 HOCH2— p-MeOPh— 33020 HOCH2— o-MeOPh— 33021 HOCH2—m-MeOPh— 33022 HOCH2— p-MePh— 33023 HOCH2— p-(CH3)2NPh— 33024 HOCH2— Ph—33025 HOCH2— p-FPh 33026 HOCH2— 3-Indolyl- 33027 HOCH2— p-AcNHPh 33028HOCH2—

33029 HOCH2—

33030 HOCH2—

[0139] TABLE 34

Example Compound No. R1— R3— 34001 CH3— p-HOPh— 34002 CH3— p-PhCH2OPh—34003 CH3— p-MeOCH2CH2OPh— 34004 CH3— p-MeOPh— 34005 CH3— o-MeOPh— 34006CH3— m-MeOPh— 34007 CH3— p-MePh— 34008 CH3— p-(CH3)2NPh— 34009 CH3— Ph—34010 CH3— p-FPh 34011 CH3— 3-Indolyl- 34012 CH3— p-AcNHPh 34013 CH3—

34014 CH3—

34015 CH3—

34016 (CH3)2CH— p-HOPh— 34017 (CH3)2CH— p-PhCH2OPh— 34018 (CH3)2CH—p-MeOCH2CH2OPh— 34019 (CH3)2CH— p-MeOPh— 34020 (CH3)2CH— o-MeOPh— 34021(CH3)2CH— m-MeOPh— 34022 (CH3)2CH— p-MePh— 34023 (CH3)2CH— p-(CH3)2NPh—34024 (CH3)2CH— Ph— 34025 (CH3)2CH— p-FPh 34026 (CH3)2CH— 3-Indolyl-34027 (CH3)2CH— p-AcNHPh 34028 (CH3)2CH—

34029 (CH3)2CH—

34030 (CH3)2CH—

[0140] TABLE 35

Example Compound No. R1— R3— 35001 PhCH2— p-HOPh— 35002 PhCH2—p-PhCH2OPh— 35003 PhCH2— p-MeOCH2CH2OPh— 35004 PhCH2— p-MeOPh— 35005PhCH2— o-MeOPh— 35006 PhCH2— m-MeOPh— 35007 PhCH2— p-MePh— 35008 PhCH2—p-(CH3)2NPh— 35009 PhCH2— Ph— 35010 PhCH2— p-FPh 35011 PhCH2— 3-Indolyl-35012 PhCH2— p-AcNHPh 35013 PhCH2—

35014 PhCH2—

35015 PhCH2—

35016 HOCH2— p-HOPh— 35017 HOCH2— p-PhCH2OPh— 35018 HOCH2—p-MeOCH2CH2OPh— 35019 HOCH2— p-MeOPh— 35020 HOCH2— o-MeOPh— 35021 HOCH2—m-MeOPh— 35022 HOCH2— p-MePh— 35023 HOCH2— p-(CH3)2NPh— 35024 HOCH2— Ph—35025 HOCH2— p-FPh 35026 HOCH2— 3-Indolyl- 35027 HOCH2— p-AcNHPh 35028HOCH2—

35029 HOCH2—

35030 HOCH2—

[0141] TABLE 36

Example Compound No. R1— R3— 36001 CH3— p-HOPh— 36002 CH3— p-PhCH2OPh—36003 CH3— p-MeOCH2CH2OPh— 36004 CH3— p-MeOPh— 36005 CH3— o-MeOPh— 36006CH3— m-MeOPh— 36007 CH3— p-MePh— 36008 CH3— p-(CH3)2NPh— 36009 CH3— Ph—36010 CH3— p-FPh 36011 CH3— 3-Indolyl- 36012 CH3— p-AcNHPh 36013 CH3—

36014 CH3—

36015 CH3—

36016 (CH3)2CH— p-HOPh— 36017 (CH3)2CH— p-PhCH2OPh— 36018 (CH3)2CH—p-MeOCH2CH2OPh— 36019 (CH3)2CH— p-MeOPh— 36020 (CH3)2CH— o-MeOPh— 36021(CH3)2CH— m-MeOPh— 36022 (CH3)2CH— p-MePh— 36023 (CH3)2CH— p-(CH3)2NPh—36024 (CH3)2CH— Ph— 36025 (CH3)2CH— p-FPh 36026 (CH3)2CH— 3-Indolyl-36027 (CH3)2CH— p-AcNHPh 36028 (CH3)2CH—

36029 (CH3)2CH—

36030 (CH3)2CH—

[0142] TABLE 37

Example Compound No. R1— R3— 37001 PhCH2— p-HOPh— 37002 PhCH2—p-PhCH2OPh— 37003 PhOH2— p-MeOCH2CH2OPh— 37004 PhCH2— p-MeOPh— 37005PhCH2— o-MeOPh— 37006 PhCH2— m-MeOPh— 37007 PhCH2— p-MePh— 37008 PhCH2—p-(CH3)2NPh— 37009 PhCH2— Ph— 37010 PhCH2— p-FPh 37011 PhCH2— 3-Indolyl-37012 PhCH2— p-AcNHPh 37013 PhCH2—

37014 PhCH2—

37015 PhCH2—

37016 HOCH2— p-HOPh— 37017 HOCH2— p-PhCH2OPh— 37018 HOCH2—p-MeOCH2CH2OPh— 37019 HOCH2— p-MeOPh— 37020 HOCH2— o-MeOPh— 37021 HOCH2—m-MeOPh— 37022 HOCH2— p-MePh— 37023 HOCH2— p-(CH3)2NPh— 37024 HOCH2— Ph—37025 HOCH2— p-FPh 37026 HOCH2— 3-Indolyl- 37027 HOCH2— p-AcNHPh 37028HOCH2—

37029 HOCH2—

37030 HOCH2—

[0143] TABLE 38

Example Compound No. R1— R3— 38001 CH3— p-HOPh— 38002 CH3— p-PhCH2OPh—38003 CH3— p-MeOCH2CH2OPh— 38004 CH3— p-MeOPh— 38005 CH3— o-MeOPh— 38006CH3— m-MeOPh— 38007 CH3— p-MePh— 38008 CH3— p-(CH3)2NPh— 38009 CH3— Ph—38010 CH3— p-FPh 38011 CH3— 3-Indolyl- 38012 CH3— p-AcNHPh 38013 CH3—

38014 CH3—

38015 CH3—

38016 (CH3)2CH— p-HOPh— 38017 (CH3)2CH— p-PhCH2OPh— 38018 (CH3)2CH—p-MeOCH2CH2OPh— 38019 (CH3)2CH— p-MeOPh— 38020 (CH3)2CH— o-MeOPh— 38021(CH3)2CH— m-MeOPh— 38022 (CH3)2CH— p-MePh— 38023 (CH3)2CH— p-(CH3)2NPh—38024 (CH3)2CH— Ph— 38025 (CH3)2CH— p-FPh 38026 (CH3)2CH— 3-Indolyl-38027 (CH3)2CH— p-AcNHPh 38028 (CH3)2CH—

38029 (CH3)2CH—

38030 (CH3)2CH—

[0144] TABLE 39

Example Compound No. R1— R3— 39001 PhCH2— p-HOPh— 39002 PhCH2—p-PhCH2OPh— 39003 PhOH2— p-MeOCH2CH2OPh— 39004 PhCH2— p-MeOPh— 39005PhCH2— o-MeOPh— 39006 PhCH2— m-MeOPh— 39007 PhCH2— p-MePh— 39008 PhCH2—p-(CH3)2NPh— 39009 PhCH2— Ph— 39010 PhCH2— p-FPh 39011 PhCH2— 3-Indolyl-39012 PhCH2— p-AcNHPh 39013 PhCH2—

39014 PhCH2—

39015 PhCH2—

39016 HOCH2— p-HOPh— 39017 HOCH2— p-PhCH2OPh— 39018 HOCH2—p-MeOCH2CH2OPh— 39019 HOCH2— p-MeOPh— 39020 HOCH2— o-MeOPh— 39021 HOCH2—m-MeOPh— 39022 HOCH2— p-MePh— 39023 HOCH2— p-(CH3)2NPh— 39024 HOCH2— Ph—39025 HOCH2— p-FPh 39026 HOCH2— 3-Indolyl- 39027 HOCH2— p-AcNHPh 39028HOCH2—

39029 HOCH2—

39030 HOCH2—

[0145] There will be described representative preparation processesaccording to this invention.

[0146] In a process for preparing a compound represented by generalformula (5) or (6) from a compound represented by general formula (1) asa starting material in this invention, the meaning of the phrase“configuration of R¹ attached to the carbon at 4-position and thesubstituent represented by a nitrogen atom in the optically active5-oxazolidinone is not changed throughout these reactions and relativeconfiguration between the amino group and the hydroxy group in theoptically active aminoalcohol represented by general formula (5) iserythro” may be described in the following reaction equations 1 and 2 indetail:

[0147] Specifically, as shown in reaction equation 1, S-form opticallyactive 5-oxazolidinone derivative represented by general formula (9)selectively gives a 1R,2S-optically active aminoalcohol derivative oferythro configuration represented by general formula (12) or (13).Furthermore, as shown in reaction formula 2, an R-form optically active5-oxazolidinone derivative represented by general formula (14) canprovide a 1S,2R-optically active aminoalcohol derivative of erythroconfiguration represented by general formula (17) or (18).

[0148] Each preparation step will be detailed.

[0149] Preparation of an Optically Active 5-Oxazolidinone DerivativeRepresented by General Formula (1)

[0150] An optically active 5-oxazolidinone derivative represented bygeneral formula (1) can be provided according to a well-known processwhere an N-urethane protected compound derived from a readily availableand inexpensive natural α-amino acid is reacted with paraformaldehyde inthe presence of a catalytic amount of an acid (J. Am. Chem. Soc. 1957,79, 5736).

[0151] Preparation of an Organometallic Reagent Represented by GeneralFormula (2)

[0152] An organometallic reagent represented by general formula (2) maybe easily prepared by a well-known process; for example, oxidativeaddition of a metal to a corresponding halogenated compound ortransmetallation with an organometallic reagent.

[0153] In preparation of an organometallic reagent, there is nolimitation of the solvent, as long as it is inert to the reaction, and,for example, ethers such as tetrahydrofuran, diethyl ether, dioxane anddiglyme; toluene; and xylenes can be used. Among these, preferred istetrahydrofuran alone or a mixture of tetrahydrofuran and anothersolvent in the light of solubility of a substrate. A reactiontemperature may be generally −78° C. to a boiling point of the solventused. Furthermore, an organometallic reagent, particularly a Grignardreagent can be used to give good results in a preparation processaccording to this invention.

[0154] A Grignard reagent may be easily prepared by, for example, addingdropwise a halogenated compound represented by R³X where X is as definedabove, after initiating the reaction by adding a catalytic amount of aninitiator such as 1,2-dibromoethane, ethyl bromide and iodine tomagnesium dispersed in a solvent.

[0155] Preparation of an Optically Active 5-HydroxyoxazolidineDerivative Represented by General Formula (3)

[0156] In a reaction of an optically active 5-oxazolidinone derivativerepresented by general formula (1) with an organometallic reagentrepresented by general formula (2), a reaction solvent may be, but notlimited to, the same solvent as that used in preparing theorganometallic reagent or a solvent mixture which does not significantlyaffect the reaction. The amount of the organometallic reagent ispreferably, but not limited to, an equal to a five-fold moles, morepreferably 1.0 to 2-fold moles per one mole of the 5-oxazolidinonederivative as a substrate. A reaction temperature may be preferably, butnot limited to, an ambient temperature, room temperature, to −78° C. Inthis reaction, there are no restrictions to the order of adding theoptically active 5-oxazolidinone derivative and the organometallicreagent. That is, the organometallic reagent may be added to theoptically active 5-oxazolidinone derivative or vice versa. At the end ofthe reaction, for obtaining the optically active 5-hydroxyoxazolidinederivative produced, the excessive organometallic reagent in thereaction solution is decomposed using, for example, an aqueous dilutedhydrochloric acid, diluted sulfuric acid, acetic acid, ammoniumchloride, citric acid or potassium hydrogen sulfate solution and thenthe product can be isolated from the resulting mixture by a commonseparation/purification process such as extraction, concentration,neutralization, filtration, recrystallization and column chromatography.

[0157] Furthermore, as described above, a Grignard reagent can be usedas an organometallic reagent to give particularly good results in thisreaction. When using a Grignard reagent as an organometallic reagent,the conditions including a reaction solvent, the amount of the materialsused, a reaction temperature, the order of adding the reagents, work-upof the reaction and isolation and purification of the product are asdescribed for the above general preparation process when using anorganometallic reagent.

[0158] The optically active 5-oxazolidine derivative prepared asdescribed above is generally obtained as a mixture of two diastereomersbecause both R- and S-forms are formed for configuration at the5-position in the oxazolidine. Depending on the conditions, highperformance liquid chromatography or nuclear magnetic spectrometry maybe performed to determine a diastereomer ratio. A diastereomer ratio mayvary depending on the reaction conditions and properties of the product,and the diastereomers may be individually isolated or may be obtained asa mixture. However, a diastereomer mixture may be converted into anoptically active aminoketone derivative represented by the same generalformula (4) by, for example, treatment with an acid described below. Itis, therefore, not necessary to separate the diastereomers as productionintermediates in the light of a production cost.

[0159] Preparation of an Optically Active Aminoketone DerivativeRepresented by General Formula (4)

[0160] A process for converting an optically active 5-hydroxyoxazolidinederivative into an optically active aminoketone derivative representedby general formula (4) under an acidic condition can be generallyconducted in a solvent. Examples of a solvent which can be used include,but not limited to, alcohols such as methanol and ethanol; acetonitrile;tetrahydrofuran; benzene; toluene; and water. These solvents may be usedalone or in combination of two or more in a given mixing ratio. Examplesof an acid which can be used include, but not limited to, inorganicacids such as hydrochloric acid, sulfuric acid and perchloric acid;organic acids such as p-toluenesulfonic acid and methanesulfonic acid;acidic resins such as Amberlite IR-120 and Amberlist; and Lewis acidssuch as boron trifluoride and zinc chloride. The amount of an acid usedis an equal to 30-fold moles, preferably 1.5- to 10-fold moles per onemole of the optically active 5-hydroxyoxazolidine derivative. When usinga resin, its amount is 5 to 200% by weight, preferably 10 to 100% byweight. A reaction temperature may be −30° C. to a boiling point of asolvent, particularly 0° C. to 100° C. An aminoketone derivative may beeasily isolated from a reaction mixture by a commonseparation/purification method such as extraction, concentration,neutralization, filtration, recrystallization and column chromatography.

[0161] Preparation of an Optically Active Aminoalcohol DerivativeRepresented by General Formula (5)

[0162] A process for reducing an aminoketone derivative represented bygeneral formula (4) with a reducing agent to give an optically activealcohol derivative represented by general formula (5) is generallyconducted in a solvent. Examples of the solvent, which can be usedinclude, but not limited to, methanol, ethanol, 2-propanol,tetrahydrofuran and water. These solvents may be used alone or incombination of two or more in a given mixing ratio.

[0163] Examples of the reducing agent include borane reagents such asborane-tetrahydrofuran complex; borohydride reagents such as sodiumborohydride, zinc borohydride and sodium trimethoxyborohydride;alkylaluminum reagents such as diisopropylaluminum hydride; aluminumhydride reagents such as lithium aluminum hydride and lithiumtrialkoxyaluminum hydride; silane reagents such as trichlorosilane andtriethylsilane; sodium metal in liquid ammonia; and magnesium metal inan alcohol. In particular, borohydride reagents such as sodiumborohydride, zinc borohydride and sodium trimethoxyborohydride aresuitable.

[0164] The amount of the reducing agent may be an equal to 10-fold molesper one mole of a material to be reduced. A reaction temperature isappropriately selected within the range of −78° C. to a boiling point ofthe solvent, preferably −40° C. to 80° C.

[0165] Alternatively, an aminoketone derivative represented by generalformula (4) may be catalytically hydrogenated in the presence of anappropriate metal catalyst in an appropriate solvent under an atmosphereof hydrogen, to give an optically active aminoalcohol derivativerepresented by general formula (5). A hydrogen pressure may be, but notlimited to, an ambient pressure to 3 MPa, preferably 0.3 MPa to 1 MPa.Any solvent may be used as long as it does not adversely affect thereaction; for example, methanol, ethanol, n-propanol, 2-propanol,n-butanol and water. These solvents may be used alone or in combinationof two or more in a given mixing ratio. The amount of a solvent is 1 to50 parts (wt/wt), preferably 3 to 20 parts per one part of thecompounds.

[0166] Examples of the metal catalyst which can be used include nickelcatalysts such as Raney nickel; platinum catalysts such asplatinum-alumina, platinum-carbon and platinum oxide; palladiumcatalysts such as palladium-alumina, palladium-carbon and palladiumhydroxide-carbon; ruthenium catalysts such as ruthenium oxide; andrhodium catalysts such as chlorotris(triphenylphosphine)rhodium which isalso known as a Wilkinson catalyst, more suitably palladium catalysts. Areaction temperature may be, but not limited to, −20 to 200° C.,preferably 0 to 60° C.

[0167] A process for deprotecting a compound represented by generalformula (5) having a protected amino group as appropriate to give a freeamine derivative represented by general formula (6) may be conducted by,for example, hydrolysis using an acid or base. Examples of an acid,which can be used include, but not limited to, inorganic acids such ashydrochloric acid, sulfuric acid and hydrobromic acid; and organic acidssuch as trifluoromethanesulfonic acid, is trifluoroacetic acid,p-toluenesulfonic acid and acetic acid. Examples of a base, which can beused, include inorganic bases such as sodium hydrogen carbonate,potassium carbonate, lithium hydroxide and sodium hydroxide; and organicbases such as triethylamine, morpholine, tetrabutylammonium fluoride andtetraethylammonium hydroxide.

[0168] An optically active aminoalcohol derivative represented bygeneral formula (5) or (6) thus obtained may be isolated as crystals ofthe free amine or as a salt by adding, if necessary, an appropriateacid. A diastereomeric purity or optical purity of the compound may beimproved by recrystallization.

[0169] When the compound is obtained as crystals of a free amine, anysolvent which is suitable to such purification can be used forcrystallization. Examples of such a solvent include alcohols such asmethanol, ethanol, n-propanol and 2-propanol; esters such as ethylacetate and butyl acetate; halogenated solvents such as chloroform andmethylene chloride; ethers such as 1,4-dioxane and tetrahydrofuran;water; acetonitrile; 2-butanone; and toluene, which can be used alone orin combination of two or more.

[0170] Any acid which can form a crystalline salt suitable forpurification may be used for salt formation. Examples of such an acidinclude inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, sulfuric acid and phosphoric acid; andorganic acids such as acetic acid, tartaric acid, citric acid, fumaricacid, methanesulfonate and p-toluenesulfonate.

[0171] Any solvent which is suitable for purification may be used forrecrystallization. Examples of such solvent include alcohols such asmethanol, ethanol, n-propanol and 2-propanol; esters such as ethylacetate and butyl acetate; halogenated solvents such as chloroform andmethylene chloride; ethers such as 1,4-dioxane and tetrahydrofuran;water; acetonitrile; 2-butanone; and toluene, which may be used alone orin combination of two or more.

[0172] A salt purified by recrystallization may be treated with analkaline solution by a common procedure to be isolated as a free amine.

EXAMPLES

[0173] This invention will be more specifically described with referenceto, but not limited to, Reference Examples and Examples.

Reference Example 1

[0174] Preparation of (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone

[0175] Benzyloxycarbonyl-L-alanine (19.3 g), paraformaldehyde (6.56 g)and p-toluenesulfonic acid monohydrate (0.17 g) were suspended intoluene (190 mL), and the mixture was heated at reflux while removingwater produced. At the end of the reaction, the reaction mixture wascooled to room temperature, washed with saturated aqueous sodiumhydrogen carbonate solution and then saturated saline. The toluenesolution was dried over anhydrous sodium sulfate. The solvent wasevaporated under a reduced pressure, the resulting crystals werefiltrated to give the title compound (19.0 g) as white crystals in anyield of 93%.

[0176] Melting point: 91-93° C. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 1.54 (d,3H, J=6.4 Hz), 4.29-4.31 (m, 1H), 5.18 (s, 2H), 5.28-5.29 (m, 1H), 5.47(br, 1H), 7.33-7.41 (m, 5H); IR (KBr) ν_(max) 1778, 1685 cm⁻¹.

Reference Example 2

[0177] Preparation of 4-benzyloxybromobenzene

[0178] p-Bromophenol (25.0 g) and anhydrous potassium carbonate (20.0 g)were suspended in N,N-dimethylformamide (250 mL). To the suspension wasadded dropwise benzyl chloride (20.2 g) at room temperature. Afterheating at 95 to 100° C. for one hour, the reaction mixture was cooledto room temperature and water (400 mL) was added. After extraction withethyl acetate, the organic layer was washed with saturated saline anddried over anhydrous sodium sulfate. The solvent was evaporated under areduced pressure to give the title compound (34.3 g) as milk-whitecrystals in a yield of 90%.

[0179] Melting point: 55-57° C.; ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 5.04 (s,2H), 6.83-6.87 (m, 2H), 7.31-7.43 (m, 2H).

Example 1

[0180] Preparation of(4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine(Compound No. 1001)

[0181] Preparation of a Grignard Reagent

[0182] To magnesium metal (1.16 g) in anhydrous tetrahydrofuran (20 mL)was added ethyl bromide (0.26 g) under nitrogen atmosphere, and themixture was stirred at room temperature for 1 hour. At reflux of thesolvent, a solution of 4-benzyloxybromobenzene (10.5 g) prepared inReference Example 2 dissolved in anhydrous tetrahydrofuran (20 mL) wasadded dropwise over about 1 hour. At the end of addition, the mixturewas stirred at reflux for further 40 min to prepare a Grignard reagent.

[0183] Grignard Reaction

[0184] In anhydrous tetrahydrofuran (40 mL) was dissolved(4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.84 g) prepared inReference Example 1 and the solution was cooled to −20° C. To thesolution under nitrogen atmosphere was added dropwise the Grignardreagent prepared above while maintaining the internal temperature at−20° C. At the end of addition, the mixture was stirred for further 1hour at that temperature, and then treated with an aqueous 5%hydrochloric acid solution. The solution was warmed to room temperatureand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate. The solution was concentrated in vacuo. Theresidue was purified by silica column chromatography (eluent:chloroform) to give the title compound (9.85 g) as a diastereomermixture as white crystals in a yield of 71%.

[0185] Melting point: 83-86° C.

[0186]¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio wasabout 2:1.

[0187] Major Diastereomer Product

[0188]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.47 (d, 3H, J=7.3 Hz), 3.81-3.84(m, 1H), 4.79-5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20(d, 1H, J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H, J=8.8 Hz),7.23-7.44 (m, 10H), 8.01 (d, 2H, J=8.8 Hz)

[0189] Sub Diastereomer Product

[0190]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.49 (d, 3H, J=7.3 Hz), 3.60-3.70(m, 1H), 4.79-5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91(d, 2H, J=8.8 Hz), 7.23-7.44 (m, 10H), 7.83 (d, 2H, J=8.8 Hz);

[0191] IR (neat) ν_(max) 3436, 3033, 1671, 1603, 1508 cm^(−1.)

Example 2

[0192] Preparation of(2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone(Compound No.: 22001)

[0193] In toluene (50 mL) was dissolved(4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine(3.8 g) prepared in Example 1. After adding Amberlist (300 mg), themixture was reacted at room temperature. At the end of the reaction,Amberlist was filtered off, the filtrate was concentrated in vacuo. Theresidue was purified by silica column chromatography (eluent:chloroform) to give the title compound (3.1 g) as pale yellow crystalsin a yield of 88%.

[0194] Melting point: 89-91° C.;

[0195]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.83 Hz), 5.13 (s,2H), 5.15 (s, 2H), 5.28-5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0Hz), 7.31-7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz);

[0196] IR (KBr) ν_(max) 3374, 1712, 1690 cm⁻¹;

[0197] Optical purity: 93%ee

[0198] HPLC Analysis Conditions:

[0199] Column: Daicel Chiral-Pak AD-RH (4.6 mmφ×150 mm);

[0200] Mobile phase: methanol;

[0201] Flow rate: 0.5 mL/min;

[0202] Wavelength: 254 nm;

[0203] Temperature: room temperature;

[0204] t_(R): (2S-form); 19.8 min;

[0205] (2R-form); 24.3 min.

Example 3

[0206] Preparation of(2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone(Compound No. 22001)

[0207] Preparation of a Grignard Reagent

[0208] To anhydrous tetrahydrofuran (15 mL) under nitrogen atmospherewere added magnesium metal (1.16 g) and ethyl bromide (0.05 g), and themixture was stirred at room temperature for 30 min. To the mixture atreflux of the solvent was added dropwise a solution of4-benzyloxybromobenzene (10.92 g) prepared in Reference Example 2dissolved in anhydrous tetrahydrofuran (10 mL) over about 1 hour. At theend of addition, the mixture was stirred at reflux for further 30 min toprepare a Grignard reagent.

[0209] Grignard Reaction

[0210] In anhydrous tetrahydrofuran (26 mL) was dissolved(4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (6.97 g) prepared inReference Example 1 and the mixture was cooled to −20° C. To thesolution under nitrogen atmosphere was added dropwise the Grignardreagent prepared above while maintaining the internal temperature at−20° C. At the end of addition, the mixture was stirred for further 1hour at that temperature.

[0211] Deformylation

[0212] To the mixture was added a 6.5% aqueous hydrochloric acidsolution, and the reaction was stirred at 35 to 40° C. for 6 hours. Theaqueous layer was discarded after separation. Then to the organic layerwas added a 5% aqueous hydrochloric acid solution, and the mixture wasstirred at 45 to 50° C. for 4 hours. The reaction mixture was extractedwith toluene and the organic layer was washed with water. The solutionwas concentrated in vacuo, 2-propanol (70 g) was added, and then themixture was stirred at room temperature for 6 hours. The reactionmixture was cooled to 0 to 5° C. to precipitate crystals, which werethen filtered to give the title compound (8.61 g) as pale yellowcrystals in a yield of 80%.

[0213] Melting point: 89-91° C.;

[0214]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.8 Hz), 5.13 (s,2H), 5.15 (s, 2H), 5.28-5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0Hz), 7.31-7.44 (m, 10H), 7.96 (d, 2H, J=9.3 Hz);

[0215] IR (KBr) ν_(max) 3374, 1712, 1690 cm⁻¹;

[0216] Specific rotation: [α]^(D) ₂₄=+26° (C=1.00, CHCl₃)

[0217] Optical purity: 99%ee (analytical conditions are as described inExample 2).

Example 4

[0218] Preparation of erythro-(1R,2S)-p-hydroxynorephedrine (CompoundNo. 28001)

[0219] A mixture of(2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (4.8g) prepared in Example 2 or 3, methanol (100 mL), water (50 mL) and 5%Pd/C (50% water-containing) (1.0 g) was stirred below 20° C. underhydrogen atmosphere (0.5 MPa) for 28 hours. The catalyst was filteredoff, the filtrate was concentrated in vacuo, and the residue was slushedwith 2-propanol to give the title compound (1.44 g) as white crystals ina yield of 70%.

[0220] Melting point: 163-165° C.;

[0221]¹H-NMR (DMSO-d₆, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.3 Hz), 2.77-2.83(m, 1H), 4.17 (d, 1H, J=5.3 Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz),7.09 (d, 2H, J=8.3 Hz), 8.31 (s, 1H);

[0222] IR (KBr) ν_(max) 3470, 1593, 1484, 1242 cm⁻¹;

[0223] Specific rotation: [α]^(D) ₂₄=−18 (C=0.2, MeOH);

[0224] Erythro: threo=99.5:0.5;

[0225] HPLC Analysis Conditions:

[0226] Column: YMC TMS A-102 (6 mmφ×150 mm)

[0227] Mobile phase: acetonitrile:water=3:97 (each of NaH₂PO₄ andNa₂HPO₄ is 10 mM, pH 6.9);

[0228] Detection wavelength: 275 nm;

[0229] Flow rate: 0.5 mL/min;

[0230] Column temperature: 40° C.;

[0231] t_(R): erythro form; 6.9 min;

[0232] threo form; 7.1 min;

[0233] Optical purity: 99%ee

[0234] HPLC Analysis Conditions:

[0235] Column: Daicel Crown-Pak CR(−) (4 mmφ×150 mm);

[0236] Mobile phase: HClO₄ aq (pH 3.5);

[0237] Detection wavelength: 275 nm;

[0238] Flow rate: 0.1 mL/min;

[0239] Column temperature: 25° C.

Example 5

[0240] Preparation oferythro-(1R,2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanol(Compound No. 36002)

[0241] To methanol (25 mL) was added sodium borohydride (0.32 g), andthe mixture was cooled to 0 to 5° C. To the solution was added(2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (2.00g) prepared in Example 2 or 3, and the mixture was stirred at roomtemperature. Precipitated crystals were filtered, washed with methanoland then dried to give the title compound (1.39 g) as white crystals ina yield of 69%.

[0242] Melting point: 85-91° C.;

[0243]¹H-NMR (DMSO-d₆, 400 MHz) δ ppm: 0.99 (d, 3H, J=6.59 Hz),3.61-3.62 (m, 1H), 4.46-4.49 (m, 1H), 4.95 (s, 2H), 5.07 (s, 2H), 5.23(m, 1H), 6.93 (d, 2H, J=7.08), 7.19-7.40 (m, 10H), 7.44 (d, 2H, J=7.08),8.30 (s, 1H);

[0244] IR (KBr) ν_(max) 3334, 1690 cm⁻¹.

Example 6

[0245] Preparation of erythro-(1R,2S)-p-hydroxynorephedrine (CompoundNo. 28001)

[0246] In methanol was dissolvederythro-(1R,2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanol(1.39 g) prepared in Example 5, and the solution was stirred with 5%Pd/C (50% water-containing) (0.03 g) under hydrogen atmosphere (ambientpressure) at room temperature for 2 hours. After removing the catalystby filtration, the filtrate was concentrated in vacuo. The residue wascrystallized with 2-propanol to give the title compound (0.65 g) aswhite crystals in a yield of 75%.

[0247] Melting point: 163-165° C.;

[0248]¹H-NMR (DMSO-d₆, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.3 Hz), 2.77-2.83(m, 1H), 4.17 (d, 1H, J=5.3 Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz),7.09 (d, 2H, J=8.3 Hz), 8.31 (s, 1H);

[0249] IR (KBr) ν_(max) 3470, 1593, 1484, 1242 cm⁻¹;

[0250] Specific rotation: [α]^(D) ₂₄=−18° (C=0.2, MeOH);

[0251] Erythro: threo=97.5:2.5 (analysis conditions are as described inExample 4);

[0252] Optical purity: 99%ee (analysis conditions are as described inExample 4).

Reference Example 3

[0253] Preparation of(4S)-N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone

[0254] In toluene (250 mL) were suspended tert-butoxycarbonyl-L-alanine(18.9 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acidmonohydrate (0.19 g), and the suspension was heated at reflux whileremoving water produced. At the end of the reaction, the mixture wascooled to room temperature, washed with saturated aqueous sodiumhydrogen carbonate solution and saturated saline. The toluene solutionwas dried over anhydrous sodium sulfate. The solvent was evaporatedunder a reduced pressure, and the crystals obtained were filtered togive the title compound (14.2 g) white crystals in a yield of 71%.

[0255] Melting point: 66-68° C.;

[0256]¹H NMR (CDCl₃, 400 MHz) δ ppm: 1.49 (s, 9H), 1.52 (d, 2H, J=7.1Hz), 4.23 (br, 1H), 5.23 (br, 1H), 5.41 (br, 1H);

[0257] IR (KBr) ν_(max) 1798, 1698 cm⁻¹.

Example 7

[0258] Preparation of(4S)-5-(4-benzyloxyphenyl)-N-tert-butoxycarbonyl-4-methyl-5-hydroxyoxazolidine(Compound No. 1015)

[0259] In anhydrous tetrahydrofuran (40 mL) was dissolved(4S)-N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone (6.64 g) prepared inReference Example 3, and the solution was cooled to −20° C. To thesolution under nitrogen atmosphere was added dropwise a Grignard reagentprepared as described in Example 1 while maintaining the internaltemperature at −20° C. At the end of addition, the mixture was stirredat that temperature for 1 hour and then treated with a 5% aqueoushydrochloric acid solution. The solution was warmed to room temperatureand extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate. The solution was concentrated in vacuo and theresidue was purified by silica column chromatography (eluent:chloroform) to give the title compound (10.2 g) as a diastereomermixture as a pale yellow syrup in an yield of 80%.

[0260]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.35-1.38 (m, 3H), 1.44-1.49 (m,9H), 4.90-5.85 (m, 5H), 6.99-7.03 (m, 2H), 7.35-7.44 (m, 5H), 7.80-8.00(m, 2H); IR (KBr) ν_(max) 3422, 1683 cm⁻¹.

Reference Example 4

[0261] Preparation of(4S)-N-benzyloxycarbonyl-4-isopropyl-5-oxazolidinone

[0262] In toluene (250 mL) were suspended benzyloxycarbonyl-L-valine(25.1 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acidmonohydrate (0.19 g), and the suspension was heated at reflux whileremoving water produced. At the end of the reaction, the mixture wascooled to room temperature, washed with saturated aqueous sodiumhydrogen carbonate solution and saturated saline. The toluene solutionwas dried over anhydrous sodium sulfate. The solvent was evaporatedunder a reduced pressure to give the title compound (23.7 g) ascolorless transparent syrup in an yield of 90%.

[0263]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.00 (d, 3H, J=6.6 Hz), 1.07 (d,3H, J=6.6 Hz), 2.30-2.40 (m, 1H), 4.22 (bs, 1H), 5.15-5.22 (m, 3H), 5.56(bs, 1H), 7.15-7.40 (m, 5H);

[0264] IR (KBr) ν_(max) 1798, 1698 cm⁻¹.

Example 8

[0265] Preparation of(4S)-5-(4-benzyloxyphenyl)-N-benzyloxycarbonyl-4-isopropyl-5-hydroxyoxazolidine(Compound No. 2001)

[0266] In anhydrous tetrahydrofuran (22 mL) was dissolved(4S)-benzyloxycarbonyl-4-isopropyl-5-oxazolidinone (5.20 g) prepared inReference Example 4, and the solution was cooled to −20° C. To thesolution under nitrogen atmosphere was added dropwise a Grignard reagentprepared as described in Example 1 while maintaining the internaltemperature at −10 to 20° C. At the end of addition, the mixture wasstirred at that temperature for 1 hour and then treated with a 12.5%aqueous hydrochloric acid solution. The solution was warmed to roomtemperature, extracted with toluene. The organic layer was dried overanhydrous magnesium sulfate. The solution was concentrated in vacuo. Theresidue was purified by silica column chromatography (eluent:hexane/ethyl acetate=2/1) to give the title compound (4.72 g) as adiastereomer mixture as a pale yellow syrup in an yield of 53%.

[0267]¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio wasabout 1.9:1.

[0268] Major Diastereomer Product

[0269]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.6 Hz), 0.98 (d,2H, J=6.6), 2.29-2.40 (m, 1H), 3.29 (m, 1H), 4.79 (m, 1H), 5.10-5.50 (m,6H), 7.02 (d, 2H, J=8.7 Hz), 7.28-7.45 (m, 10H), 8.11 (d, 2H, J=8.7 Hz);

[0270] Sub Diastereomer Product

[0271]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 0.83 (d, 3H, J=6.2 Hz), 1.00 (d,2H, J=6.2), 2.29-2.40 (m, 1H), 3.55 (m, 1H), 4.79 (m, 1H), 5.10-5.50 (m,6H), 6.81 (d, 2H, J=9.0 Hz), 7.28-7.45 (m, 10H), 7.85 (d, 2H, J=9.0 Hz);

[0272] IR (KBr) ν_(max) 3422, 1683 cm⁻¹

Example 9

[0273] Preparation of(2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-3-methyl-1-butanone(Compound No. 23001)

[0274] In tetrahydrofuran (4 mL) was dissolved(4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-isopropyl-5-hydroxyoxazolidine(1.38 g) prepared in Example 8, and to the solution were added water (5mL) and conc. hydrochloric acid (2 mL). The mixture was stirred at roomtemperature for 24 hours. The reaction was diluted with toluene and theaqueous layer was discarded. The organic layer was washed with waterthree times. The organic layer was dried over anhydrous magnesiumsulfate and then concentrated in vacuo. The residue was purified bysilica column chromatography (eluent: hexane/ethyl acetate=2/1) to givethe title compound (466 mg) as pale yellow crystals in a yield of 36%.

[0275] Melting point: 75-77° C.;

[0276]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 0.76 (d, 3H, J=6.8 Hz), 1.04 (d,3H, J=6.8 Hz), 2.16 (m, 1H), 5.11 (s, 1H), 5.14 (s, 1H), 5.24 (dd, 1H,J=8.8, 4 Hz), 5.70 (d, 1H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz), 7.30-7.45(m, 10H), 7.96 (d, 2H, J=8.8 Hz);

[0277] IR (KBr) ν_(max) 3422, 1683 cm⁻¹.

Example 10

[0278] Preparation of(4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine(Compound No. 1020)

[0279] Preparation of a Grignard Reagent

[0280] To anhydrous tetrahydrofuran (20 mL) under nitrogen atmospherewere added magnesium metal (756 mg) and ethyl bromide (0.1 g), and themixture was stirred at room temperature for 1 hour. To the mixture atreflux of the solvent was added dropwise a solution of 4-bromoanisole(3.76 g) dissolved in anhydrous tetrahydrofuran (20 mL) over 1 hour. Atthe end of addition, the mixture was stirred at reflux for further 40min to prepare a Grignard reagent.

[0281] Grignard Reaction

[0282] In anhydrous tetrahydrofuran (30 mL) was dissolved(4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.70 g) prepared inReference Example 1, and the solution was cooled to −20° C. To thesolution under nitrogen atmosphere was added dropwise the Grignardreagent while maintaining the internal temperature at −20° C. At the endof addition, the mixture was stirred for 1 hour at that temperature andthen treated with a 5% aqueous hydrochloric acid solution. The solutionwas warmed to room temperature and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate. The solution wasconcentrated in vacuo. The residue was purified by silica columnchromatography (eluent: hexane/ethyl acetate=2/1 to 3/2), to give thetitle compound (4.56 g) as a diastereomer mixture as a colorlesstransparent syrup in a yield of 66%.

[0283]¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio wasabout 2:1.

[0284] Major Diastereomer Product

[0285]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.47 (d, 3H, J=7 Hz), 3.70-3.75 (m,1H), 3.87 (s, 3H), 4.80-5.20 (m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d,1H, J=12.4 Hz), 5.88 (q, 1H, J=7 Hz), 6.95 (d, 2H, J=9.0 Hz), 7.23-7.36(m, 5H), 8.02 (d, 2H, J=9.0 Hz);

[0286] Minor Diastereomer Product

[0287]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.48 (d, 3H, J=7 Hz), 3.70-3.75 (m,1H), 3.86 (s, 3H), 4.80-5.20 (m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d,1H, J=12.4 Hz), 5.57 (q, 1H, J=7 Hz), 6.83 (d, 2H, J=8.8 Hz), 7.23-7.36(m, 5H), 8.83 (d, 2H, J=8.8 Hz)

[0288] IR (neat) ν_(max) 3443, 1697, 1601 cm⁻¹.

Example 11

[0289] Preparation of(2S)-2-(benzyloxycarbonyl)amino-1-(4-methoxyphenyl)-1-propanone(Compound No. 22020)

[0290] In tetrahydrofuran (4 mL) was dissolved(4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine(1.72 g) prepared in Example 10 and then water (5 mL) and conc.hydrochloric acid (2 mL) were added. The mixture was stirred at roomtemperature for 24 hours. The reaction was diluted with toluene, theaqueous layer was discarded, and then the organic layer was dried overanhydrous magnesium sulfate. After concentration under a reducedpressure, the residue was purified by silica column chromatography(eluent: hexane/ethyl acetate=3/1) to give the title compound (1.40 mg)as white crystals in a yield of 89%.

[0291] Melting point: 46-48° C.;

[0292]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.8 Hz), 3.88 (s,3H), 5.13 (s, 2H), 5.30 (dq, 1H, J=7.1, 6.8 Hz), 5.91 (d, 1H, J=7.1 Hz),6.96 (d, 2H, J=8.8 Hz), 7.29-7.37 (m, 5H), 7.96 (d, 2H, J=8.8 Hz);

[0293] IR (KBr) ν_(max) 3458, 2958, 1714, 1676, 1597, 1527 cm⁻¹.

Example 12

[0294] Preparation of(4S)-N-benzyloxycarbonyl-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine(Compound No. 1030)

[0295] Preparation of a Grignard Reagent

[0296] To anhydrous tetrahydrofuran (20 mL) under nitrogen atmospherewere added magnesium metal (2.56 g) and iodine (30 mg). To the mixtureat room temperature was added one-fifth of a solution of2,4-difluorobromobenzene (19.3 g) dissolved in anhydrous tetrahydrofuran(60 mL) in one portion. Five minutes after addition, Grignard reagentformation was initiated as indicated by temperature rising of thereaction. While maintaining a reaction temperature below 45° C., theremaining four-fifths of the reagent was added dropwise over about 30min. At the end of addition, the mixture was stirred at 25 to 40° C. for30 min to give a Grignard reagent.

[0297] Grignard Reaction

[0298] In anhydrous tetrahydrofuran (68 mL) was dissolved(4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (21.2 g) prepared inReference Example 1, and the solution was cooled to −20° C. To thesolution under nitrogen atmosphere was added dropwise the Grignardreagent prepared while maintaining the internal temperature at −20° C.At the end of addition, the mixture was stirred at that temperature forone hour and treated with a 5% aqueous hydrochloric acid solution. Thesolution was warmed to room temperature and extracted with toluene. Theorganic layer was dried over anhydrous magnesium sulfate. The solutionwas concentrated in vacuo. The residue was purified by silica columnchromatography (eluent: hexane/ethyl acetate=2/1) to give the titlecompound (21.4 g) as a diastereomer mixture as a pale yellow syrup in ayield of 68%.

[0299]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.52 and 1.51 (2d, 3H, J=6.8 Hz),3.20-3.45 (m, 1H), 4.30-4.50 (m, 1H), 4.70-5.45 (m, 4H), 6.55-6.90 (m,2H), 7.30-7.40 (m, 5H), 7.50-7.90 (m, 1H);

[0300] IR (KBr) ν_(max) 3402, 1803, 1701, 1614 cm⁻¹.

Example 13

[0301] Preparation of(2S)-2-(benzyloxycarbonyl)amino-1-(2,4-difluorophenyl)-1-propanone(Compound No. 22030)

[0302] In tetrahydrofuran (70 mL) was dissolved(4S)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine(14.0 g) prepared in Example 12, and water (50 mL) and conc.hydrochloric acid (20 mL) were added. The mixture was stirred at roomtemperature for 24 hours. The reaction mixture was diluted with toluene,the aqueous layer was discarded, and the organic layer was washed withwater three times. The organic layer was dried over anhydrous magnesiumsulfate and concentrated in vacuo. The residue was purified by silicacolumn chromatography (eluent: hexane/ethyl acetate=3/1) to give thetitle compound (11.7 g) as a pale yellow syrup in a yield of 92%.

[0303]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.40 (d, 3H, J=7.0 Hz), 5.10 (s,2H), 5.05-5.20 (m, 1H), 5.75-5.80 (m, 1H), 6.88-6.94 (m, 1H), 6.98-7.02(m, 1H), 7.30-7.37 (m, 5H), 7.95-8.01 (m, 1H);

[0304] IR (neat) ν_(max) 3358, 1718, 1681, 1611, 1532 cm⁻¹,

[0305] Optical purity: 90%ee;

[0306] HPLC Analysis Conditions

[0307] Column: Daicel Chiral-Pak AD-RH (4.6 mmφ×150 mm);

[0308] Mobile phase: methanol;

[0309] Flow rate: 0.5 mL/min;

[0310] Wavelength: 254 nm;

[0311] Temperature: room temperature;

[0312] t_(R): (2R-form); 6.5 min

[0313] (2S-form); 7.5 min.

Reference Example 5

[0314] Preparation of (4R)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone

[0315] In toluene (190 mL) were suspended benzyloxycarbonyl-D-alanine(19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acidmonohydrate (0.17 g), and the mixture was heated at reflux whileremoving water produced. At the end of the reaction, the mixture wascooled to room temperature, and washed with saturated aqueous sodiumhydrogen carbonate solution and saturated saline. The toluene solutionwas dried over anhydrous sodium sulfate. The solvent was evaporatedunder a reduced pressure. The precipitated crystals were filtered togive the title compound (17.4 g) as white crystals in a yield of 85%.

[0316] Melting point: 89-91° C.;

[0317]¹H NMR (CDCl₃, 400 MHz) δ ppm: 1.54 (d, 3H, J=6.4 Hz), 4.29-4.31(m, 1H), 5.18 (s, 2H), 5.28-5.29 (m, 1H), 5.47 (br, 1H), 7.33-7.41 (m,5H);

[0318] IR (KBr) ν_(max) 1778, 1685 cm⁻¹.

Example 14

[0319] Preparation of(4R)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine(Compound No. 19001)

[0320] (4R)-N-Benzyloxycarbonyl-4-methyl-5-oxazolidinone (2.61 g)prepared in Reference Example 5 was processed as described in Example 1to give the title compound (9.0 g) as a diastereomer mixture as whitecrystals in an yield of 65%.

[0321] Melting point: 82-86° C.

[0322]¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio wasabout 2:1.

[0323] Major Diastereomer Product

[0324]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.47 (d, 3H, J=7.3 Hz), 3.81-3.84(m, 1H), 4.79-5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20(d, 1H, J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H, J=8.8 Hz),7.23-7.44 (m, 10H), 8.01 (d, 2H, J=8.8 Hz);

[0325] Sub Diastereomer Product

[0326]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.49 (d, 3H, J=7.3 Hz), 3.60-3.70(m, 1H), 4.79-5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91(d, 2H, J=8.8 Hz), 7.23-7.44 (m, 10H), 7.83 (d, 2H, J=8.8 Hz);

[0327] IR (neat) ν_(max) 3436, 3033, 1671, 1603, 1508 cm⁻¹.

Example 15

[0328] Preparation of(2R)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone(Compound No. 25001)

[0329](4R)-N-Benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine(2.1 g) prepared in Example 14 was processed as described in Example 9to give the title compound (1.85 g) as pale yellow crystals in an yieldof 95%.

[0330] Melting point: 88-90° C.;

[0331]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.83 Hz), 5.13 (s,2H), 5.15 (s, 2H), 5.28-5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0Hz), 7.31-7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz);

[0332] IR (KBr) ν_(max) 3374, 1712, 1690 cm⁻¹;

[0333] Specific rotation: [α]^(D) ₂₄=−25° (C=1.00, CHCl₃);

[0334] Optical purity: 98%ee (analysis conditions are as described inExample 3).

Example 16

[0335] Preparation of(4R)-N-benzyloxycarbonyl-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine(Compound No. 19030)

[0336] Preparation of a Grignard Reagent

[0337] To anhydrous tetrahydrofuran (10 mL) under nitrogen atmospherewere added magnesium metal (1.28 g) and iodine (20 mg). A solution of2,4-difluorobromobenzene (9.65 g) in anhydrous tetrahydrofuran (30 mL)at room temperature was used as described in Example 12 to give aGrignard reagent.

[0338] Grignard Reaction

[0339] In anhydrous tetrahydrofuran (34 mL) was dissolved(4R)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (10.6 g). The mixturewas processed as described in Example 12 to give the title compound(10.7 g) as a diastereomer mixture as a pale yellow syrup in a yield of68%.

[0340]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.52 and 1.51 (2d, 3H, J=6.8 Hz),3.20-3.45 (m, 1H), 4.30-4.50 (m, 1H), 4.70-5.45 (m, 4H), 6.55-6.90 (m,2H), 7.30-7.40 (m, 5H), 7.50-7.90 (m, 1H);

[0341] IR (KBr) ν_(max) 3402, 1803, 1701, 1614 cm⁻¹.

Example 17

[0342] Preparation of(2R)-2-(benzyloxycarbonyl)amino-1-(2,4-difluorophenyl)-1-propanone(Compound No. 25030)

[0343] In tetrahydrofuran (35 mL) was dissolved(4R)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine(6.98 g) prepared in Example 16, and water (25 mL) and conc.hydrochloric acid (10 mL) were added. The mixture was processed asdescribed in Example 13 to give the title compound (5.87 g) as paleyellow syrup in a yield of 92%.

[0344]¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.40 (d, 3H, J=7.0 Hz), 5.10 (s,2H), 5.05-5.20 (m, 1H), 5.75-5.80 (m, 1H), 6.88-6.94 (m, 1H), 6.98-7.02(m, 1H), 7.30-7.37 (m, 5H), 7.95-8.01 (m, 1H);

[0345] IR (neat) ν_(max) 3358, 1718, 1681, 1611, 1532 cm⁻¹;

[0346] Optical purity: 90%ee (analysis conditions are as described inExample 12).

INDUSTRIAL APPLICABILITY

[0347] According to the present invention, an optically activeaminoalcohol derivative represented by general formula (5) or (6), whichis useful as a production intermediate for a medicine or agriculturalagent, can be produced stably in a large scale with an industriallyadequate optical purity and a lower cost. This invention also providesan optically active 5-hydroxyoxazolidine derivative represented bygeneral formula (3) as an important intermediate for production of theabove optically active aminoalcohol derivative or other optically activeamine derivatives and a generally usable preparation process therefor,as well as an optically aminoketone derivative represented by generalformula (4) and a generally usable preparation process therefor. Theproduction technique may be extensively applicable to preparation ofoptically active amine derivatives in addition to preparation of theabove optically active aminoalcohol derivative, and thus is industriallyexcellent technique.

What is claimed is:
 1. A process for preparing an optically activeaminoalcohol wherein an optically active 5-oxazolidinone derivativerepresented by a general formula (1):

wherein R¹ represents an unprotected or optionally protected side chainin a natural α-amino acid; and R² represents optionally substituted arylor optionally substituted aralkyl, is reacted with an organometallicreagent represented by general formula (2): R³—M  (2) wherein R³represents optionally substituted aryl or optionally substitutedheterocycle; M represents one selected from the group consisting of Li,MgX, ZnX, TiX₃ and CuX; and X represents halogen, to form an opticallyactive 5-hydroxyoxazolidine derivative represented by general formula(3):

wherein R¹, R² and R³ are as defined above, which is then treated underacidic conditions to give an optically active aminoketone derivativerepresented by general formula (4):

wherein R¹ and R³ are as defined above; and R⁴ represents hydrogen oroptionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group, which is then treated with a reducing agent orcatalytically hydrogenated with a metal catalyst to stereoselectivelyprovide an optically active aminoalcohol derivative represented bygeneral formula (5):

wherein R¹, R³ and R⁴ are as defined above; provided that configurationof R¹ attached to the asymmetric carbon at 4-position and thesubstituent represented by a nitrogen atom in the optically active5-oxazolidinone represented by general formula (1) is not changedthroughout these reactions and relative configuration between the aminogroup and the hydroxy group in the optically active aminoalcoholrepresented by general formula (5) is an erythro configuration.
 2. Aprocess for preparing an aminoalcohol wherein an optically active5-oxazolidinone derivative represented by a general formula (1):

wherein R¹ represents an unprotected or optionally protected side chainin a natural α-amino acid; and R² represents optionally substituted arylor optionally substituted aralkyl, is reacted with an organometallicreagent represented by general formula (2): R³—M  (2) wherein R³represents optionally substituted aryl or optionally substitutedheterocycle; M represents one selected from the group consisting of Li,MgX, ZnX, TiX₃ and CuX; and X represents halogen, to form an opticallyactive 5-hydroxyoxazolidine derivative represented by general formula(3):

wherein R¹, R² and R³ are as defined above, which is then treated underacidic conditions to give an optically active aminoketone derivativerepresented by general formula (4):

wherein R¹ and R³ are as defined above; and R⁴ represents hydrogen oroptionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group, which is then treated with a reducing agent orcatalytically hydrogenated with a metal catalyst to provide an opticallyactive aminoalcohol derivative represented by general formula (5):

wherein R¹, R³ and R⁴ are as defined above, and then, when R⁴ is aprotective group, the amino group in the product is deprotected to givean optically active aminoalcohol derivative represented by generalformula (6):

wherein R¹ and R³ are as defined above; provided that configuration ofR¹ attached to the asymmetric carbon at 4-position and the substituentrepresented by a nitrogen atom in the optically active 5-oxazolidinonerepresented by general formula (1) is not changed throughout thesereactions and relative configuration between the amino group and thehydroxy group in the optically active aminoalcohol represented bygeneral formula (6) is an erythro configuration.
 3. The process forpreparing an optically active aminoalcohol as claimed in claim 1 or 2wherein R¹ represents methyl, isopropyl, isobutyl, benzyl,hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl,alkyloxycarbonylmethyl or alkyloxycarbonylethyl; R² represents benzyl,tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.
 4. Theprocess for preparing an optically active aminoalcohol as claimed inclaim 1 or 2 wherein R³ is represented by general formula (7):

wherein Y represents halogen; or by general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted phenyl, optionally substituted heterocycle or optionallysubstituted heterocyclealkyl.
 5. The process for preparing an opticallyactive aminoalcohol derivative as claimed in claim 1 or 2 wherein R¹represents methyl; and R³ is represented by general formula (8).
 6. Anoptically active 5-hydroxyoxazolidine derivative represented by generalformula (3):

wherein R¹ represents an unprotected side chain or optionally protectedside chain in a natural α-amino acid; R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl; and R³ represents optionally substituted aryl or optionallysubstituted heterocycle.
 7. The optically active 5-hydroxyoxazolidinederivative as claimed in claim 6 wherein R¹ represents methyl,isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl,phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl oralkyloxycarbonylethyl.
 8. The optically active 5-hydroxyoxazolidinederivative as claimed in claim 6 or 7 wherein R² represents benzyl,tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.
 9. Theoptically active 5-hydroxyoxazolidine derivative as claimed in claim 8wherein R³ is represented by general formula (7):

wherein Y represents halogen; or general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted phenyl, optionally substituted heterocycle or optionallysubstituted heterocyclealkyl.
 10. The optically active5-hydroxyoxazolidine derivative as claimed in claim 9 wherein R¹ ismethyl.
 11. A process for preparing an optically active5-hydroxyoxazolidine derivative wherein an optically active5-oxazolidinone derivative represented by general formula (1):

wherein R¹ represents an unprotected side chain or optionally protectedside chain in a natural α-amino acid; R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl, is reacted with an organometallic reagent represented bygeneral formula (2): R³—M  (2) wherein R³ represents optionallysubstituted aryl or optionally substituted heterocycle; M is oneselected from the group consisting of Li, MgX, ZnX, TiX₃ and CuX; and Xrepresents halogen, to provide an optically active 5-hydroxyoxazolidinederivative represented by general formula (3):

wherein R¹, R² and R³ are as defined above.
 12. The process forpreparing an optically active 5-hydroxyoxazolidine derivative as claimedin claim 11 wherein R¹ represents methyl, isopropyl, isobutyl, benzyl,hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl,alkyloxycarbonylmethyl or alkyloxycarbonylethyl.
 13. The process forpreparing an optically active 5-hydroxyoxazolidine derivative as claimedin claim 11 or 12 wherein R² represents benzyl, tert-butyl, methyl,ethyl, isopropyl or 9-fluorenylmethyl.
 14. The process for preparing anoptically active 5-hydroxyoxazolidine derivative as claimed in claim 13wherein R³ is represented by general formula (7):

wherein Y represents halogen; or general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted phenyl, optionally substituted heterocycle or optionallysubstituted heterocyclealkyl.
 15. The process for preparing an opticallyactive 5-hydroxyoxazolidine derivative as claimed in claim 14 wherein R¹is methyl.
 16. The process for preparing an optically active5-hydroxyoxazolidine derivative as claimed in claim 11 or 12 wherein Min general formula (2) is MgX wherein X is as defined above.
 17. Anaminoketone derivative represented by general formula (4a):

wherein R^(1a) represents methyl; R^(4a) represents hydrogen,benzyloxycarbonyl, tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl;R^(3a) represents 4-benzyloxyphenyl, 4-methoxyphenyl,2,4-difluorophenyl, 2,4-dichlorophenyl or 3-indolyl.
 18. A process forpreparing an aminoketone derivative wherein a 5-hydroxyoxazolidinederivative represented by general formula (3):

wherein R¹ represents an unprotected side chain or optionally protectedside chain in a natural α-amino acid; R² represents optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedaralkyl; and R³ represents optionally substituted aryl or optionallysubstituted heterocycle, is treated under acidic conditions to form anaminoketone derivative represented by general formula (4):

wherein R¹ and R³ are as defined above; R⁴ represents hydrogen oroptionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group.
 19. An optically active alcohol derivative representedby general formula (5a):

wherein R^(1a) represents methyl; R^(3b) represents 4-benzyloxyphenyl;R^(4b) represents benzyloxycarbonyl; and configuration between the aminogroup and the hydroxy group is an erythro configuration.
 20. A processfor preparing an optically active aminoalcohol derivative wherein anoptically active aminoketone derivative represented by general formula(4b):

wherein R¹ represents an unprotected side chain or optionally protectedside chain in a natural α-amino acid; R⁴ represents hydrogen oroptionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group; R^(3c) is represented by general formula (8):

R⁵ represents hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted phenyl, optionally substituted heterocycle or optionallysubstituted heterocyclealkyl, is treated with a reducing agent orcatalytically hydrogenated with a metal catalyst, to stereoselectivelyform an optically active aminoalcohol derivative represented by generalformula (5b):

wherein R¹, R^(3c) and R⁴ are as defined above; provided thatconfiguration of R¹ attached to the asymmetric carbon at 2-position andthe substituent represented by a nitrogen atom in the optically activeaminoketone derivative represented by general formula (4b) is notchanged throughout these reactions and relative configuration betweenthe amino group and the hydroxy group in the optically activeaminoalcohol derivative represented by general formula (5b) is anerythro configuration.
 21. A process for preparing an optically activeaminoalcohol derivative wherein an optically active aminoketonederivative represented by general formula (4b):

wherein R¹ represents an unprotected side chain or optionally protectedside chain in a natural α-amino acid; R⁴ represents hydrogen oroptionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl or optionally substituted aralkyloxycarbonyl as aprotective group; R^(3c) is represented by general formula (8):

R⁵ represents hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted phenyl, optionally substituted heterocycle or optionallysubstituted heterocyclealkyl, is treated with a reducing agent orcatalytically hydrogenated with a metal catalyst, to stereoselectivelyform an optically active aminoalcohol represented by general formula(5b):

wherein R¹, R^(3c) and R⁴ are as defined above, and when R⁴ is aprotective group, the amino group in the product is deprotected to givean optically active aminoalcohol derivative represented by generalformula (6a):

wherein R¹ and R^(3c) are as defined above; provided that configurationof R¹ attached to the asymmetric carbon at 2-position and thesubstituent represented by a nitrogen atom in the optically activeaminoketone derivative represented by general formula (4b) is notchanged throughout these reactions and relative configuration betweenthe amino group and the hydroxy group in the optically activeaminoalcohol derivative represented by general formula (6a) is anerythro configuration.